The Experts below are selected from a list of 852 Experts worldwide ranked by ideXlab platform

Zirong Chen - One of the best experts on this subject based on the ideXlab platform.

  • CRTC1 maml2 fusion induced lncrna linc00473 expression maintains the growth and survival of human mucoepidermoid carcinoma cells
    Oncogene, 2018
    Co-Authors: Zirong Chen, Frederic J Kaye, Jianliang Li, Wei Ni, Jianrong Lu, Lizi Wu
    Abstract:

    Mucoepidermoid carcinoma (MEC) arises in many glandular tissues and contributes to the most common malignant salivary gland cancers. MEC is specifically associated with a unique t(11;19) translocation and the resulting CRTC1-MAML2 fusion is a major oncogenic driver for MEC initiation and maintenance. However, the molecular basis underlying the CRTC1-MAML2 oncogenic functions remains elusive. Through gene expression profiling analysis, we observed that LINC00473, a long non-coding RNA (lncRNA), was the top down-regulated target in CRTC1-MAML2-depleted human MEC cells. LncRNAs belong to a new class of non-coding RNAs with emerging roles in tumorigenesis and progression, but remain poorly characterized. In this study, we investigated the role of LINC00473 in mediating CRTC1-MAML2 oncogenic activity in human MEC. We found that LINC00473 transcription was significantly induced in human CRTC1-MAML2-positive MEC cell lines and primary MEC tumors, and was tightly correlated with the CRTC1-MAML2 RNA level. LINC00473 induction was dependent on the ability of CRTC1-MAML2 to activate CREB-mediated transcription. Depletion of LINC00473 significantly reduced the proliferation and survival of human MEC cells in vitro and blocked the in vivo tumor growth in a human MEC xenograft model. RNA in situ hybridization analysis demonstrated a predominantly nuclear localization pattern for LINC00473 in human MEC cells. Furthermore, gene expression profiling revealed that LINC00473 depletion resulted in differential expression of genes important in cancer cell growth and survival. LINC00473 likely regulates gene expression in part through its ability to bind to a cAMP signaling pathway component NONO, enhancing the ability of CRTC1-MAML2 to activate CREB-mediated transcription. Our overall results demonstrate that LINC00473 is a downstream target and an important mediator of the CRTC1-MAML2 oncoprotein. Therefore, LINC00473 acts as a promising biomarker and therapeutic target for human CRTC1-MAML2-positive MECs.

  • abstract a22 an lkb1 CRTC1 circuit regulates glycosylated cox 2 and predicts drug response in lung cancer
    Molecular Cancer Research, 2016
    Co-Authors: Min Zhang, Antonio L Amelio, Mohammad Fallahi, Zirong Chen, Yumei Gu, Chengbin Hu, Eric A Welsh, Brienne E Engel, Eric B Haura, Douglas W Cress
    Abstract:

    Cyclooxygenase-2 (COX-2) directs the synthesis of prostaglandins important for mitogenic signaling. Here we report that COX-2 is a transcriptional target of the CREB co-activator CRTC1. In addition, we detected a correlation between the LKB1-null status and presence of 72/74 kDa glycosylated COX-2, but not inactive hypoglycosylated COX-2 in fresh lung adenocarcinoma samples. Since CRTC1 is suppressed by cytoplasmic shuttling following LKB1/AMPK/SIK phosphorylation, we developed an LKB1 signature in lung cancer to search the Connectivity-MAP drug response database. Remarkably, all high-ranking drugs positively associated with the LKB1-null signature were known CRTC1 activators. Somatic LKB1 mutations are present in 20% of lung adenocarcinomas and we observed growth and cell motility inhibition with COX-2 inhibitors in LKB1-null lung cancer cells with activated CRTC1, but negligible inhibition in LKB1-wildtype cells. In summary, the CREB co-activator CRTC family directly links LKB1 with COX-2 activation and provides a new framework for selecting patients for COX-2 inhibition. Citation Format: Chunxia Cao, Ruli Gao, Min Zhang, Antonio L. Amelio, Mohammad Fallahi, Zirong Chen, Yumei Gu, Chengbin Hu, Eric A. Welsh, Brienne E. Engel, Eric Haura, W. Douglas Cress, Lizi Wu, Maria Zajac-Kaye, Frederic J. Kaye. An LKB1-CRTC1 circuit regulates glycosylated COX-2 and predicts drug response in lung cancer. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A22.

  • gene expression profiling analysis of CRTC1 maml2 fusion oncogene induced transcriptional program in human mucoepidermoid carcinoma cells
    BMC Cancer, 2015
    Co-Authors: Jie Chen, Zirong Chen, Jianliang Li, James D Griffin, Lizi Wu
    Abstract:

    Mucoepidermoid carcinoma (MEC) arises from multiple organs and accounts for the most common types of salivary gland malignancies. Currently, patients with unresectable and metastatic MEC have poor long-term clinical outcomes and no targeted therapies are available. The majority of MEC tumors contain a t(11;19) chromosomal translocation that fuses two genes, CRTC1 and MAML2, to generate the chimeric protein CRTC1-MAML2. CRTC1-MAML2 displays transforming activity in vitro and is required for human MEC cell growth and survival, partially due to its ability to constitutively activate CREB-mediated transcription. Consequently, CRTC1-MAML2 is implicated as a major etiologic molecular event and a therapeutic target for MEC. However, the molecular mechanisms underlying CRTC1-MAML2 oncogenic action in MEC have not yet been systematically analyzed. Elucidation of the CRTC1-MAML2-regulated transcriptional program and its underlying mechanisms will provide important insights into MEC pathogenesis that are essential for the development of targeted therapeutics. Transcriptional profiling was performed on human MEC cells with the depletion of endogenous CRTC1-MAML2 fusion or its interacting partner CREB via shRNA-mediated gene knockdown. A subset of target genes was validated via real-time RT-PCR assays. CRTC1-MAML2-perturbed molecular pathways in MEC were identified through pathway analyses. Finally, comparative analysis of CRTC1-MAML2-regulated and CREB-regulated transcriptional profiles was carried out to assess the contribution of CREB in mediating CRTC1-MAML2-induced transcription. A total of 808 differentially expressed genes were identified in human MEC cells after CRTC1-MAML2 knockdown and a subset of known and novel fusion target genes was confirmed by real-time RT-PCR. Pathway Analysis revealed that CRTC1-MAML2-regulated genes were associated with network functions that are important for cell growth, proliferation, survival, migration, and metabolism. Comparison of CRTC1-MAML2-regulated and CREB-regulated transcriptional profiles revealed common and distinct genes regulated by CRTC1-MAML2 and CREB, respectively. This study identified a specific CRTC1-MAML2-induced transcriptional program in human MEC cells and demonstrated that CRTC1-MAML2 regulates gene expression in CREB-dependent and independent manners. Our data provide the molecular basis underlying CRTC1-MAML2 oncogenic functions and lay a foundation for further functional investigation of CRTC1-MAML2-induced signaling in MEC initiation and maintenance.

  • abstract 166 identification of a novel long noncoding rna as a mediator for CRTC1 maml2 fusion oncogenic function and a biomarker for CRTC1 maml2 fusion positive tumors
    Cancer Research, 2015
    Co-Authors: Zirong Chen, Frederic J Kaye, Jianliang Li, Lizi Wu
    Abstract:

    Long non-coding RNAs (LncRNA) are non-protein coding transcripts longer than 200 nucleotides and represent a novel class of gene regulators. LncRNA expression is frequently de-regulated in cancer. Specific lncRNAs have been shown to participate in cancer cell proliferation, survival, migration, and invasion, and targeting these cancer-associated lncRNAs inhibits tumor growth and metastasis. Therefore, lncRNAs are implicated as cancer biomarkers and therapeutic targets. The human genome encodes >10,000 lncRNAs; however, only a handful lncRNAs have been well characterized. We revealed through a microarray analysis that a novel lncRNA, lnc473 is a top target for the CRTC1-MAML2 fusion oncogene. CRTC1-MAML2 is generated by a t(11;19)(q21;p13) translocation that is specifically associated with mucoepidermoid carcinoma (MEC). MEC is a distinct type of tumors containing three cellular components, squamous cells, mucus-secreting cells, and intermediate cells. MEC occurs in many glandular tissues and accounts for the most common salivary gland malignancies. The CRTC1-MAML2 functions as a transcriptional co-activator, capable of promoting transcription from CREB and other factors. CRTC1-MAML2 is a major oncogenic driver for MEC initiation and maintenance. Currently, knowledge remains limited regarding how CRTC1-MAML2 mediates its oncogenic activity. In this study, we studied the regulatory mechanism of lnc473 expression and its function in mediating CRTC1-MAML2 oncogenic activity. We observed that lnc473 expression was tightly correlated with CRTC1-MAML2 fusion expression levels in human MEC cell lines and primary tumors using a Nanostring assay that allowed direct digital quantification of RNA molecules, strongly suggesting that lnc473 is a surrogate marker for functional CRTC1-MAML2 fusion. Lentiviral shRNA-mediated depletion of endogenous CRTCT1-MAML2 and its interacting transcription factor CREB resulted in a significant reduction of lnc473 expression. Also, lnc473 contained conserved CREB-binding sites on its proximal promoter, suggesting that CRTC1-MAML2 interacts with CREB in promoting lnc473 transcription. Functionally, depletion of lnc473 significantly reduced human MEC cell proliferation and survival in vitro and blocked the growth of MEC xenograft tumors. Our combined findings indicate that this lnc473 is a biomarker for human CRTC1-MAML2-positive MEC and has a novel regulatory function in mediating CRTC1-MAML2 cancer gene activity. Intriguingly, lnc473 depletion reduced expression of several known CRTC1-MAML2/CREB target genes, suggesting that lnc473 exerts a positive feedback regulation of CRTC1-MAML2-mediated transcription. The molecular mechanisms underlying lnc473 functions in MEC are currently being investigated through analyses of lnc473-regulated targeted gene profiling and lncRNA interacting protein complexes Citation Format: Zirong Chen, Jian-Liang Li, Shuibin Lin, Chunxia Cao, Frederic Kaye, Lizi Wu. Identification of a novel long noncoding RNA as a mediator for CRTC1-MAML2 fusion oncogenic function and a biomarker for CRTC1-MAML2 fusion-positive tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 166. doi:10.1158/1538-7445.AM2015-166

  • abstract 2284 generation and characterization of a mouse model of CRTC1 maml2 induced mucoepidermoid carcinoma mec
    Cancer Research, 2015
    Co-Authors: Zirong Chen, Frederic J Kaye, Yumei Gu, Jianliang Li, Wei Ni, Maria D Hurtado, Sergei Zolotukhin, Lizi Wu
    Abstract:

    Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy and can arise in multiple other organ sites. Currently, patients with advanced, unresectable MEC have limited therapeutic options and poor treatment outcomes. Clinical improvement has been hindered by a lack of understanding of the basic mechanisms underlying MEC development as well as suitable preclinical models. The majority of MEC tumors contain a t(11;19)(q21;p13) chromosomal translocation that results in the generation of a new fusion gene product, CRTC1-MAML2. We previously showed that the CRTC1-MAML2 fusion had a strong transcriptional co-activator activity and was capable of transforming epithelial cells in vitro, in part through co-activating the transcription factor CREB. Depletion of CRTC1-MAML2 fusion expression reduced the growth and survival of human malignant MEC cells when assayed in vitro or when propagated as xenograft tumors in vivo. These findings indicate that CRTC1-MAML2 is essential in maintaining MEC malignant phenotype and serves as a promising therapeutic target. However, whether CRTC1-MAML2 fusion has a causal role in MEC induction had not been demonstrated in vivo. In this study, we determined the oncogenic potential of the CRTC1-MAML2 fusion in vivo by establishing a Cre-regulated CRTC1-MAML2 transgenic mouse model. Through genetic crossing with MMTV-Cre mice or direct AAV-Cre transduction to induce expression of CRTC1-MAML2 transgene in salivary glandular cells, the transgenic mice developed salivary gland tumors with typical human MEC histological characteristics. Moreover, isolated tumor cells were capable of forming subcutaneous tumors in immune-compromised hosts that again recapitulate the MEC histological feature. Transcriptome analysis revealed that mouse tumors showed differential expression of genes associated with cell growth, survival, and metastasis as well as host cell immune modulating pathways in comparison with tumor-adjacent, macroscopically normal salivary gland tissues and salivary gland tissues from fusion transgene-negative littermate controls. Importantly, CRTC1-MAML2-induced tumors showed enhanced expression of known fusion target genes in human MEC, strongly supporting that this mouse tumor model molecularly resembles human MEC. Therefore, our study offered a direct proof for an oncogenic role of CRTC1-MAML2 fusion in vivo and provided the first genetically engineered mouse model for human MEC. Using this mouse MEC model, we are currently dissecting oncogenic transformation of normal salivary gland stem cells by salisphere assays, identifying cooperative genetic alterations in MEC through whole exome sequencing, and assessing its utility as a preclinical MEC model in evaluating therapeutic strategies. Citation Format: Zirong Chen, Jian-Liang Li, Shuibin Lin, Dinglong Pan, Wei Ni, Chunxia Cao, Yumei Gu, Maria Daniela Hurtado, Sergei Zolotukhin, Tao Sun, Frederic Kaye, Lizi Wu. Generation and characterization of a mouse model of CRTC1-MAML2-induced mucoepidermoid carcinoma (MEC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2284. doi:10.1158/1538-7445.AM2015-2284

James D Griffin - One of the best experts on this subject based on the ideXlab platform.

  • gene expression profiling analysis of CRTC1 maml2 fusion oncogene induced transcriptional program in human mucoepidermoid carcinoma cells
    BMC Cancer, 2015
    Co-Authors: Jie Chen, Zirong Chen, Jianliang Li, James D Griffin, Lizi Wu
    Abstract:

    Mucoepidermoid carcinoma (MEC) arises from multiple organs and accounts for the most common types of salivary gland malignancies. Currently, patients with unresectable and metastatic MEC have poor long-term clinical outcomes and no targeted therapies are available. The majority of MEC tumors contain a t(11;19) chromosomal translocation that fuses two genes, CRTC1 and MAML2, to generate the chimeric protein CRTC1-MAML2. CRTC1-MAML2 displays transforming activity in vitro and is required for human MEC cell growth and survival, partially due to its ability to constitutively activate CREB-mediated transcription. Consequently, CRTC1-MAML2 is implicated as a major etiologic molecular event and a therapeutic target for MEC. However, the molecular mechanisms underlying CRTC1-MAML2 oncogenic action in MEC have not yet been systematically analyzed. Elucidation of the CRTC1-MAML2-regulated transcriptional program and its underlying mechanisms will provide important insights into MEC pathogenesis that are essential for the development of targeted therapeutics. Transcriptional profiling was performed on human MEC cells with the depletion of endogenous CRTC1-MAML2 fusion or its interacting partner CREB via shRNA-mediated gene knockdown. A subset of target genes was validated via real-time RT-PCR assays. CRTC1-MAML2-perturbed molecular pathways in MEC were identified through pathway analyses. Finally, comparative analysis of CRTC1-MAML2-regulated and CREB-regulated transcriptional profiles was carried out to assess the contribution of CREB in mediating CRTC1-MAML2-induced transcription. A total of 808 differentially expressed genes were identified in human MEC cells after CRTC1-MAML2 knockdown and a subset of known and novel fusion target genes was confirmed by real-time RT-PCR. Pathway Analysis revealed that CRTC1-MAML2-regulated genes were associated with network functions that are important for cell growth, proliferation, survival, migration, and metabolism. Comparison of CRTC1-MAML2-regulated and CREB-regulated transcriptional profiles revealed common and distinct genes regulated by CRTC1-MAML2 and CREB, respectively. This study identified a specific CRTC1-MAML2-induced transcriptional program in human MEC cells and demonstrated that CRTC1-MAML2 regulates gene expression in CREB-dependent and independent manners. Our data provide the molecular basis underlying CRTC1-MAML2 oncogenic functions and lay a foundation for further functional investigation of CRTC1-MAML2-induced signaling in MEC initiation and maintenance.

  • aberrantly activated areg egfr signaling is required for the growth and survival of CRTC1 maml2 fusion positive mucoepidermoid carcinoma cells
    Oncogene, 2014
    Co-Authors: Zirong Chen, Frederic J Kaye, Yumei Gu, Chengbin Hu, Jianliang Li, Huangxuan Shen, Patick K Ha, Janejane Chen, Jing Li, James D Griffin
    Abstract:

    Aberrantly activated AREG–EGFR signaling is required for the growth and survival of CRTC1–MAML2 fusion-positive mucoepidermoid carcinoma cells

  • abstract 3026 targeting aberrantly activated areg egfr signaling in CRTC1 maml2 positive mucoepidermoid carcinoma
    Cancer Research, 2013
    Co-Authors: Zirong Chen, Yumei Gu, Chengbin Hu, Jianliang Li, Jie Chen, Huangxuan Shen, Jiancheng Li, Patick K Ha, Federic J Kaye, James D Griffin
    Abstract:

    Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Salivary gland tumors (SGT) are a group of highly heterogeneous head and neck malignancies with widely varied clinical outcomes and no standard effective treatments. The CRTC1-MAML2 gene fusion, encoded by a recurring chromosomal translocation t(11;19)(q14-21;p12-13), is a highly specific genetic alteration in more than 50% of mucoepidermoid carcinoma (MEC), the most common malignant SGT. In this study, we aimed to define the role of the CRTC1-MAML2 oncogene in the maintenance of MEC tumor growth and to investigate critical downstream target genes and pathways for therapeutic targeting of MEC. By performing gene expression analyses and functional studies via RNA interference and pharmacological modulation, we determined the importance of the CRTC1-MAML2 fusion gene and its downstream AREG-EGFR signaling in human MEC cancer cell growth ad survival in vitro and in vivo using human MEC xenograft models. We found that CRTC1-MAML2 fusion oncogene was required for the growth and survival of fusion-positive human MEC cancer cells in vitro and the in vivo. CRTC1-MAML2 induced the up-regulation of the EGFR ligand AREG by co-activating the transcription factor CREB and AREG subsequently activated EGFR signaling in an autocrine manner that promoted MEC cell growth and survival. Importantly, CRTC1-MAML2-positive MEC cells were highly sensitive to EGFR signaling inhibition. Therefore, our study revealed that aberrantly activated AREG-EGFR signaling is required for CRTC1-MAML2-positive MEC cell growth and survival, suggesting that EGFR-targeted therapies will benefit patients with unresectable CRTC1-MAML2-positive MEC. Citation Format: Zirong Chen, Yumei Gu, Chengbin Hu, Jian-Liang Li, Shuibin Lin, Huangxuan Shen, Chunxia Cao, Jie Chen, Jiancheng Li, Patick K. Ha, Federic J. Kaye, James D. Griffin, Lizi Wu. Targeting aberrantly activated AREG-EGFR signaling in CRTC1-MAML2-positive mucoepidermoid carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3026. doi:10.1158/1538-7445.AM2013-3026

Frederic J Kaye - One of the best experts on this subject based on the ideXlab platform.

  • CRTC1 maml2 fusion induced lncrna linc00473 expression maintains the growth and survival of human mucoepidermoid carcinoma cells
    Oncogene, 2018
    Co-Authors: Zirong Chen, Frederic J Kaye, Jianliang Li, Wei Ni, Jianrong Lu, Lizi Wu
    Abstract:

    Mucoepidermoid carcinoma (MEC) arises in many glandular tissues and contributes to the most common malignant salivary gland cancers. MEC is specifically associated with a unique t(11;19) translocation and the resulting CRTC1-MAML2 fusion is a major oncogenic driver for MEC initiation and maintenance. However, the molecular basis underlying the CRTC1-MAML2 oncogenic functions remains elusive. Through gene expression profiling analysis, we observed that LINC00473, a long non-coding RNA (lncRNA), was the top down-regulated target in CRTC1-MAML2-depleted human MEC cells. LncRNAs belong to a new class of non-coding RNAs with emerging roles in tumorigenesis and progression, but remain poorly characterized. In this study, we investigated the role of LINC00473 in mediating CRTC1-MAML2 oncogenic activity in human MEC. We found that LINC00473 transcription was significantly induced in human CRTC1-MAML2-positive MEC cell lines and primary MEC tumors, and was tightly correlated with the CRTC1-MAML2 RNA level. LINC00473 induction was dependent on the ability of CRTC1-MAML2 to activate CREB-mediated transcription. Depletion of LINC00473 significantly reduced the proliferation and survival of human MEC cells in vitro and blocked the in vivo tumor growth in a human MEC xenograft model. RNA in situ hybridization analysis demonstrated a predominantly nuclear localization pattern for LINC00473 in human MEC cells. Furthermore, gene expression profiling revealed that LINC00473 depletion resulted in differential expression of genes important in cancer cell growth and survival. LINC00473 likely regulates gene expression in part through its ability to bind to a cAMP signaling pathway component NONO, enhancing the ability of CRTC1-MAML2 to activate CREB-mediated transcription. Our overall results demonstrate that LINC00473 is a downstream target and an important mediator of the CRTC1-MAML2 oncoprotein. Therefore, LINC00473 acts as a promising biomarker and therapeutic target for human CRTC1-MAML2-positive MECs.

  • abstract 166 identification of a novel long noncoding rna as a mediator for CRTC1 maml2 fusion oncogenic function and a biomarker for CRTC1 maml2 fusion positive tumors
    Cancer Research, 2015
    Co-Authors: Zirong Chen, Frederic J Kaye, Jianliang Li, Lizi Wu
    Abstract:

    Long non-coding RNAs (LncRNA) are non-protein coding transcripts longer than 200 nucleotides and represent a novel class of gene regulators. LncRNA expression is frequently de-regulated in cancer. Specific lncRNAs have been shown to participate in cancer cell proliferation, survival, migration, and invasion, and targeting these cancer-associated lncRNAs inhibits tumor growth and metastasis. Therefore, lncRNAs are implicated as cancer biomarkers and therapeutic targets. The human genome encodes >10,000 lncRNAs; however, only a handful lncRNAs have been well characterized. We revealed through a microarray analysis that a novel lncRNA, lnc473 is a top target for the CRTC1-MAML2 fusion oncogene. CRTC1-MAML2 is generated by a t(11;19)(q21;p13) translocation that is specifically associated with mucoepidermoid carcinoma (MEC). MEC is a distinct type of tumors containing three cellular components, squamous cells, mucus-secreting cells, and intermediate cells. MEC occurs in many glandular tissues and accounts for the most common salivary gland malignancies. The CRTC1-MAML2 functions as a transcriptional co-activator, capable of promoting transcription from CREB and other factors. CRTC1-MAML2 is a major oncogenic driver for MEC initiation and maintenance. Currently, knowledge remains limited regarding how CRTC1-MAML2 mediates its oncogenic activity. In this study, we studied the regulatory mechanism of lnc473 expression and its function in mediating CRTC1-MAML2 oncogenic activity. We observed that lnc473 expression was tightly correlated with CRTC1-MAML2 fusion expression levels in human MEC cell lines and primary tumors using a Nanostring assay that allowed direct digital quantification of RNA molecules, strongly suggesting that lnc473 is a surrogate marker for functional CRTC1-MAML2 fusion. Lentiviral shRNA-mediated depletion of endogenous CRTCT1-MAML2 and its interacting transcription factor CREB resulted in a significant reduction of lnc473 expression. Also, lnc473 contained conserved CREB-binding sites on its proximal promoter, suggesting that CRTC1-MAML2 interacts with CREB in promoting lnc473 transcription. Functionally, depletion of lnc473 significantly reduced human MEC cell proliferation and survival in vitro and blocked the growth of MEC xenograft tumors. Our combined findings indicate that this lnc473 is a biomarker for human CRTC1-MAML2-positive MEC and has a novel regulatory function in mediating CRTC1-MAML2 cancer gene activity. Intriguingly, lnc473 depletion reduced expression of several known CRTC1-MAML2/CREB target genes, suggesting that lnc473 exerts a positive feedback regulation of CRTC1-MAML2-mediated transcription. The molecular mechanisms underlying lnc473 functions in MEC are currently being investigated through analyses of lnc473-regulated targeted gene profiling and lncRNA interacting protein complexes Citation Format: Zirong Chen, Jian-Liang Li, Shuibin Lin, Chunxia Cao, Frederic Kaye, Lizi Wu. Identification of a novel long noncoding RNA as a mediator for CRTC1-MAML2 fusion oncogenic function and a biomarker for CRTC1-MAML2 fusion-positive tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 166. doi:10.1158/1538-7445.AM2015-166

  • abstract 2284 generation and characterization of a mouse model of CRTC1 maml2 induced mucoepidermoid carcinoma mec
    Cancer Research, 2015
    Co-Authors: Zirong Chen, Frederic J Kaye, Yumei Gu, Jianliang Li, Wei Ni, Maria D Hurtado, Sergei Zolotukhin, Lizi Wu
    Abstract:

    Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy and can arise in multiple other organ sites. Currently, patients with advanced, unresectable MEC have limited therapeutic options and poor treatment outcomes. Clinical improvement has been hindered by a lack of understanding of the basic mechanisms underlying MEC development as well as suitable preclinical models. The majority of MEC tumors contain a t(11;19)(q21;p13) chromosomal translocation that results in the generation of a new fusion gene product, CRTC1-MAML2. We previously showed that the CRTC1-MAML2 fusion had a strong transcriptional co-activator activity and was capable of transforming epithelial cells in vitro, in part through co-activating the transcription factor CREB. Depletion of CRTC1-MAML2 fusion expression reduced the growth and survival of human malignant MEC cells when assayed in vitro or when propagated as xenograft tumors in vivo. These findings indicate that CRTC1-MAML2 is essential in maintaining MEC malignant phenotype and serves as a promising therapeutic target. However, whether CRTC1-MAML2 fusion has a causal role in MEC induction had not been demonstrated in vivo. In this study, we determined the oncogenic potential of the CRTC1-MAML2 fusion in vivo by establishing a Cre-regulated CRTC1-MAML2 transgenic mouse model. Through genetic crossing with MMTV-Cre mice or direct AAV-Cre transduction to induce expression of CRTC1-MAML2 transgene in salivary glandular cells, the transgenic mice developed salivary gland tumors with typical human MEC histological characteristics. Moreover, isolated tumor cells were capable of forming subcutaneous tumors in immune-compromised hosts that again recapitulate the MEC histological feature. Transcriptome analysis revealed that mouse tumors showed differential expression of genes associated with cell growth, survival, and metastasis as well as host cell immune modulating pathways in comparison with tumor-adjacent, macroscopically normal salivary gland tissues and salivary gland tissues from fusion transgene-negative littermate controls. Importantly, CRTC1-MAML2-induced tumors showed enhanced expression of known fusion target genes in human MEC, strongly supporting that this mouse tumor model molecularly resembles human MEC. Therefore, our study offered a direct proof for an oncogenic role of CRTC1-MAML2 fusion in vivo and provided the first genetically engineered mouse model for human MEC. Using this mouse MEC model, we are currently dissecting oncogenic transformation of normal salivary gland stem cells by salisphere assays, identifying cooperative genetic alterations in MEC through whole exome sequencing, and assessing its utility as a preclinical MEC model in evaluating therapeutic strategies. Citation Format: Zirong Chen, Jian-Liang Li, Shuibin Lin, Dinglong Pan, Wei Ni, Chunxia Cao, Yumei Gu, Maria Daniela Hurtado, Sergei Zolotukhin, Tao Sun, Frederic Kaye, Lizi Wu. Generation and characterization of a mouse model of CRTC1-MAML2-induced mucoepidermoid carcinoma (MEC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2284. doi:10.1158/1538-7445.AM2015-2284

  • aberrantly activated areg egfr signaling is required for the growth and survival of CRTC1 maml2 fusion positive mucoepidermoid carcinoma cells
    Oncogene, 2014
    Co-Authors: Zirong Chen, Frederic J Kaye, Yumei Gu, Chengbin Hu, Jianliang Li, Huangxuan Shen, Patick K Ha, Janejane Chen, Jing Li, James D Griffin
    Abstract:

    Aberrantly activated AREG–EGFR signaling is required for the growth and survival of CRTC1–MAML2 fusion-positive mucoepidermoid carcinoma cells

  • CRTC1 expression during normal and abnormal salivary gland development supports a precursor cell origin for mucoepidermoid cancer
    Gene Expression Patterns, 2011
    Co-Authors: Tina Jaskoll, Frederic J Kaye, Khine Htet, George Abichaker, Michael Melnick
    Abstract:

    Dysregulation of the transcription factor CRTC1 by a t(11;19) chromosomal rearrangement mediates the formation of mucoepidermoid salivary gland carcinoma (MEC). Although the CRTC1 promoter is consistently active in fusion-positive MEC and low levels of CRTC1 transcripts have been reported in normal adult salivary glands, the distribution of CRTC1 protein in the normal salivary gland is not known. The aim of this study was to determine if CRTC1, like many known oncogenes, is expressed during early submandibular salivary gland (SMG) development and re-expressed in an experimental tumor model. Our results indicate that CRTC1 protein is expressed in SMG epithelia during early stages of morphogenesis, disappears with differentiation, and reappears in initial tumor-like pathology. This stage-dependent expression pattern suggests that CRTC1 may play a role during embryonic SMG branching morphogenesis but not for pro-acinar/acinar differentiation, supporting a precursor cell origin for MEC tumorigenesis. Moreover, the coincident expression of CRTC1 protein and cell proliferation markers in tumor-like histopathology suggests that CRTC1-mediated cell proliferation may contribute, in part, to initial tumor formation.

Jianliang Li - One of the best experts on this subject based on the ideXlab platform.

  • CRTC1 maml2 fusion induced lncrna linc00473 expression maintains the growth and survival of human mucoepidermoid carcinoma cells
    Oncogene, 2018
    Co-Authors: Zirong Chen, Frederic J Kaye, Jianliang Li, Wei Ni, Jianrong Lu, Lizi Wu
    Abstract:

    Mucoepidermoid carcinoma (MEC) arises in many glandular tissues and contributes to the most common malignant salivary gland cancers. MEC is specifically associated with a unique t(11;19) translocation and the resulting CRTC1-MAML2 fusion is a major oncogenic driver for MEC initiation and maintenance. However, the molecular basis underlying the CRTC1-MAML2 oncogenic functions remains elusive. Through gene expression profiling analysis, we observed that LINC00473, a long non-coding RNA (lncRNA), was the top down-regulated target in CRTC1-MAML2-depleted human MEC cells. LncRNAs belong to a new class of non-coding RNAs with emerging roles in tumorigenesis and progression, but remain poorly characterized. In this study, we investigated the role of LINC00473 in mediating CRTC1-MAML2 oncogenic activity in human MEC. We found that LINC00473 transcription was significantly induced in human CRTC1-MAML2-positive MEC cell lines and primary MEC tumors, and was tightly correlated with the CRTC1-MAML2 RNA level. LINC00473 induction was dependent on the ability of CRTC1-MAML2 to activate CREB-mediated transcription. Depletion of LINC00473 significantly reduced the proliferation and survival of human MEC cells in vitro and blocked the in vivo tumor growth in a human MEC xenograft model. RNA in situ hybridization analysis demonstrated a predominantly nuclear localization pattern for LINC00473 in human MEC cells. Furthermore, gene expression profiling revealed that LINC00473 depletion resulted in differential expression of genes important in cancer cell growth and survival. LINC00473 likely regulates gene expression in part through its ability to bind to a cAMP signaling pathway component NONO, enhancing the ability of CRTC1-MAML2 to activate CREB-mediated transcription. Our overall results demonstrate that LINC00473 is a downstream target and an important mediator of the CRTC1-MAML2 oncoprotein. Therefore, LINC00473 acts as a promising biomarker and therapeutic target for human CRTC1-MAML2-positive MECs.

  • gene expression profiling analysis of CRTC1 maml2 fusion oncogene induced transcriptional program in human mucoepidermoid carcinoma cells
    BMC Cancer, 2015
    Co-Authors: Jie Chen, Zirong Chen, Jianliang Li, James D Griffin, Lizi Wu
    Abstract:

    Mucoepidermoid carcinoma (MEC) arises from multiple organs and accounts for the most common types of salivary gland malignancies. Currently, patients with unresectable and metastatic MEC have poor long-term clinical outcomes and no targeted therapies are available. The majority of MEC tumors contain a t(11;19) chromosomal translocation that fuses two genes, CRTC1 and MAML2, to generate the chimeric protein CRTC1-MAML2. CRTC1-MAML2 displays transforming activity in vitro and is required for human MEC cell growth and survival, partially due to its ability to constitutively activate CREB-mediated transcription. Consequently, CRTC1-MAML2 is implicated as a major etiologic molecular event and a therapeutic target for MEC. However, the molecular mechanisms underlying CRTC1-MAML2 oncogenic action in MEC have not yet been systematically analyzed. Elucidation of the CRTC1-MAML2-regulated transcriptional program and its underlying mechanisms will provide important insights into MEC pathogenesis that are essential for the development of targeted therapeutics. Transcriptional profiling was performed on human MEC cells with the depletion of endogenous CRTC1-MAML2 fusion or its interacting partner CREB via shRNA-mediated gene knockdown. A subset of target genes was validated via real-time RT-PCR assays. CRTC1-MAML2-perturbed molecular pathways in MEC were identified through pathway analyses. Finally, comparative analysis of CRTC1-MAML2-regulated and CREB-regulated transcriptional profiles was carried out to assess the contribution of CREB in mediating CRTC1-MAML2-induced transcription. A total of 808 differentially expressed genes were identified in human MEC cells after CRTC1-MAML2 knockdown and a subset of known and novel fusion target genes was confirmed by real-time RT-PCR. Pathway Analysis revealed that CRTC1-MAML2-regulated genes were associated with network functions that are important for cell growth, proliferation, survival, migration, and metabolism. Comparison of CRTC1-MAML2-regulated and CREB-regulated transcriptional profiles revealed common and distinct genes regulated by CRTC1-MAML2 and CREB, respectively. This study identified a specific CRTC1-MAML2-induced transcriptional program in human MEC cells and demonstrated that CRTC1-MAML2 regulates gene expression in CREB-dependent and independent manners. Our data provide the molecular basis underlying CRTC1-MAML2 oncogenic functions and lay a foundation for further functional investigation of CRTC1-MAML2-induced signaling in MEC initiation and maintenance.

  • abstract 166 identification of a novel long noncoding rna as a mediator for CRTC1 maml2 fusion oncogenic function and a biomarker for CRTC1 maml2 fusion positive tumors
    Cancer Research, 2015
    Co-Authors: Zirong Chen, Frederic J Kaye, Jianliang Li, Lizi Wu
    Abstract:

    Long non-coding RNAs (LncRNA) are non-protein coding transcripts longer than 200 nucleotides and represent a novel class of gene regulators. LncRNA expression is frequently de-regulated in cancer. Specific lncRNAs have been shown to participate in cancer cell proliferation, survival, migration, and invasion, and targeting these cancer-associated lncRNAs inhibits tumor growth and metastasis. Therefore, lncRNAs are implicated as cancer biomarkers and therapeutic targets. The human genome encodes >10,000 lncRNAs; however, only a handful lncRNAs have been well characterized. We revealed through a microarray analysis that a novel lncRNA, lnc473 is a top target for the CRTC1-MAML2 fusion oncogene. CRTC1-MAML2 is generated by a t(11;19)(q21;p13) translocation that is specifically associated with mucoepidermoid carcinoma (MEC). MEC is a distinct type of tumors containing three cellular components, squamous cells, mucus-secreting cells, and intermediate cells. MEC occurs in many glandular tissues and accounts for the most common salivary gland malignancies. The CRTC1-MAML2 functions as a transcriptional co-activator, capable of promoting transcription from CREB and other factors. CRTC1-MAML2 is a major oncogenic driver for MEC initiation and maintenance. Currently, knowledge remains limited regarding how CRTC1-MAML2 mediates its oncogenic activity. In this study, we studied the regulatory mechanism of lnc473 expression and its function in mediating CRTC1-MAML2 oncogenic activity. We observed that lnc473 expression was tightly correlated with CRTC1-MAML2 fusion expression levels in human MEC cell lines and primary tumors using a Nanostring assay that allowed direct digital quantification of RNA molecules, strongly suggesting that lnc473 is a surrogate marker for functional CRTC1-MAML2 fusion. Lentiviral shRNA-mediated depletion of endogenous CRTCT1-MAML2 and its interacting transcription factor CREB resulted in a significant reduction of lnc473 expression. Also, lnc473 contained conserved CREB-binding sites on its proximal promoter, suggesting that CRTC1-MAML2 interacts with CREB in promoting lnc473 transcription. Functionally, depletion of lnc473 significantly reduced human MEC cell proliferation and survival in vitro and blocked the growth of MEC xenograft tumors. Our combined findings indicate that this lnc473 is a biomarker for human CRTC1-MAML2-positive MEC and has a novel regulatory function in mediating CRTC1-MAML2 cancer gene activity. Intriguingly, lnc473 depletion reduced expression of several known CRTC1-MAML2/CREB target genes, suggesting that lnc473 exerts a positive feedback regulation of CRTC1-MAML2-mediated transcription. The molecular mechanisms underlying lnc473 functions in MEC are currently being investigated through analyses of lnc473-regulated targeted gene profiling and lncRNA interacting protein complexes Citation Format: Zirong Chen, Jian-Liang Li, Shuibin Lin, Chunxia Cao, Frederic Kaye, Lizi Wu. Identification of a novel long noncoding RNA as a mediator for CRTC1-MAML2 fusion oncogenic function and a biomarker for CRTC1-MAML2 fusion-positive tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 166. doi:10.1158/1538-7445.AM2015-166

  • abstract 2284 generation and characterization of a mouse model of CRTC1 maml2 induced mucoepidermoid carcinoma mec
    Cancer Research, 2015
    Co-Authors: Zirong Chen, Frederic J Kaye, Yumei Gu, Jianliang Li, Wei Ni, Maria D Hurtado, Sergei Zolotukhin, Lizi Wu
    Abstract:

    Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy and can arise in multiple other organ sites. Currently, patients with advanced, unresectable MEC have limited therapeutic options and poor treatment outcomes. Clinical improvement has been hindered by a lack of understanding of the basic mechanisms underlying MEC development as well as suitable preclinical models. The majority of MEC tumors contain a t(11;19)(q21;p13) chromosomal translocation that results in the generation of a new fusion gene product, CRTC1-MAML2. We previously showed that the CRTC1-MAML2 fusion had a strong transcriptional co-activator activity and was capable of transforming epithelial cells in vitro, in part through co-activating the transcription factor CREB. Depletion of CRTC1-MAML2 fusion expression reduced the growth and survival of human malignant MEC cells when assayed in vitro or when propagated as xenograft tumors in vivo. These findings indicate that CRTC1-MAML2 is essential in maintaining MEC malignant phenotype and serves as a promising therapeutic target. However, whether CRTC1-MAML2 fusion has a causal role in MEC induction had not been demonstrated in vivo. In this study, we determined the oncogenic potential of the CRTC1-MAML2 fusion in vivo by establishing a Cre-regulated CRTC1-MAML2 transgenic mouse model. Through genetic crossing with MMTV-Cre mice or direct AAV-Cre transduction to induce expression of CRTC1-MAML2 transgene in salivary glandular cells, the transgenic mice developed salivary gland tumors with typical human MEC histological characteristics. Moreover, isolated tumor cells were capable of forming subcutaneous tumors in immune-compromised hosts that again recapitulate the MEC histological feature. Transcriptome analysis revealed that mouse tumors showed differential expression of genes associated with cell growth, survival, and metastasis as well as host cell immune modulating pathways in comparison with tumor-adjacent, macroscopically normal salivary gland tissues and salivary gland tissues from fusion transgene-negative littermate controls. Importantly, CRTC1-MAML2-induced tumors showed enhanced expression of known fusion target genes in human MEC, strongly supporting that this mouse tumor model molecularly resembles human MEC. Therefore, our study offered a direct proof for an oncogenic role of CRTC1-MAML2 fusion in vivo and provided the first genetically engineered mouse model for human MEC. Using this mouse MEC model, we are currently dissecting oncogenic transformation of normal salivary gland stem cells by salisphere assays, identifying cooperative genetic alterations in MEC through whole exome sequencing, and assessing its utility as a preclinical MEC model in evaluating therapeutic strategies. Citation Format: Zirong Chen, Jian-Liang Li, Shuibin Lin, Dinglong Pan, Wei Ni, Chunxia Cao, Yumei Gu, Maria Daniela Hurtado, Sergei Zolotukhin, Tao Sun, Frederic Kaye, Lizi Wu. Generation and characterization of a mouse model of CRTC1-MAML2-induced mucoepidermoid carcinoma (MEC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2284. doi:10.1158/1538-7445.AM2015-2284

  • aberrantly activated areg egfr signaling is required for the growth and survival of CRTC1 maml2 fusion positive mucoepidermoid carcinoma cells
    Oncogene, 2014
    Co-Authors: Zirong Chen, Frederic J Kaye, Yumei Gu, Chengbin Hu, Jianliang Li, Huangxuan Shen, Patick K Ha, Janejane Chen, Jing Li, James D Griffin
    Abstract:

    Aberrantly activated AREG–EGFR signaling is required for the growth and survival of CRTC1–MAML2 fusion-positive mucoepidermoid carcinoma cells

Yumei Gu - One of the best experts on this subject based on the ideXlab platform.

  • abstract a22 an lkb1 CRTC1 circuit regulates glycosylated cox 2 and predicts drug response in lung cancer
    Molecular Cancer Research, 2016
    Co-Authors: Min Zhang, Antonio L Amelio, Mohammad Fallahi, Zirong Chen, Yumei Gu, Chengbin Hu, Eric A Welsh, Brienne E Engel, Eric B Haura, Douglas W Cress
    Abstract:

    Cyclooxygenase-2 (COX-2) directs the synthesis of prostaglandins important for mitogenic signaling. Here we report that COX-2 is a transcriptional target of the CREB co-activator CRTC1. In addition, we detected a correlation between the LKB1-null status and presence of 72/74 kDa glycosylated COX-2, but not inactive hypoglycosylated COX-2 in fresh lung adenocarcinoma samples. Since CRTC1 is suppressed by cytoplasmic shuttling following LKB1/AMPK/SIK phosphorylation, we developed an LKB1 signature in lung cancer to search the Connectivity-MAP drug response database. Remarkably, all high-ranking drugs positively associated with the LKB1-null signature were known CRTC1 activators. Somatic LKB1 mutations are present in 20% of lung adenocarcinomas and we observed growth and cell motility inhibition with COX-2 inhibitors in LKB1-null lung cancer cells with activated CRTC1, but negligible inhibition in LKB1-wildtype cells. In summary, the CREB co-activator CRTC family directly links LKB1 with COX-2 activation and provides a new framework for selecting patients for COX-2 inhibition. Citation Format: Chunxia Cao, Ruli Gao, Min Zhang, Antonio L. Amelio, Mohammad Fallahi, Zirong Chen, Yumei Gu, Chengbin Hu, Eric A. Welsh, Brienne E. Engel, Eric Haura, W. Douglas Cress, Lizi Wu, Maria Zajac-Kaye, Frederic J. Kaye. An LKB1-CRTC1 circuit regulates glycosylated COX-2 and predicts drug response in lung cancer. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A22.

  • abstract 2284 generation and characterization of a mouse model of CRTC1 maml2 induced mucoepidermoid carcinoma mec
    Cancer Research, 2015
    Co-Authors: Zirong Chen, Frederic J Kaye, Yumei Gu, Jianliang Li, Wei Ni, Maria D Hurtado, Sergei Zolotukhin, Lizi Wu
    Abstract:

    Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy and can arise in multiple other organ sites. Currently, patients with advanced, unresectable MEC have limited therapeutic options and poor treatment outcomes. Clinical improvement has been hindered by a lack of understanding of the basic mechanisms underlying MEC development as well as suitable preclinical models. The majority of MEC tumors contain a t(11;19)(q21;p13) chromosomal translocation that results in the generation of a new fusion gene product, CRTC1-MAML2. We previously showed that the CRTC1-MAML2 fusion had a strong transcriptional co-activator activity and was capable of transforming epithelial cells in vitro, in part through co-activating the transcription factor CREB. Depletion of CRTC1-MAML2 fusion expression reduced the growth and survival of human malignant MEC cells when assayed in vitro or when propagated as xenograft tumors in vivo. These findings indicate that CRTC1-MAML2 is essential in maintaining MEC malignant phenotype and serves as a promising therapeutic target. However, whether CRTC1-MAML2 fusion has a causal role in MEC induction had not been demonstrated in vivo. In this study, we determined the oncogenic potential of the CRTC1-MAML2 fusion in vivo by establishing a Cre-regulated CRTC1-MAML2 transgenic mouse model. Through genetic crossing with MMTV-Cre mice or direct AAV-Cre transduction to induce expression of CRTC1-MAML2 transgene in salivary glandular cells, the transgenic mice developed salivary gland tumors with typical human MEC histological characteristics. Moreover, isolated tumor cells were capable of forming subcutaneous tumors in immune-compromised hosts that again recapitulate the MEC histological feature. Transcriptome analysis revealed that mouse tumors showed differential expression of genes associated with cell growth, survival, and metastasis as well as host cell immune modulating pathways in comparison with tumor-adjacent, macroscopically normal salivary gland tissues and salivary gland tissues from fusion transgene-negative littermate controls. Importantly, CRTC1-MAML2-induced tumors showed enhanced expression of known fusion target genes in human MEC, strongly supporting that this mouse tumor model molecularly resembles human MEC. Therefore, our study offered a direct proof for an oncogenic role of CRTC1-MAML2 fusion in vivo and provided the first genetically engineered mouse model for human MEC. Using this mouse MEC model, we are currently dissecting oncogenic transformation of normal salivary gland stem cells by salisphere assays, identifying cooperative genetic alterations in MEC through whole exome sequencing, and assessing its utility as a preclinical MEC model in evaluating therapeutic strategies. Citation Format: Zirong Chen, Jian-Liang Li, Shuibin Lin, Dinglong Pan, Wei Ni, Chunxia Cao, Yumei Gu, Maria Daniela Hurtado, Sergei Zolotukhin, Tao Sun, Frederic Kaye, Lizi Wu. Generation and characterization of a mouse model of CRTC1-MAML2-induced mucoepidermoid carcinoma (MEC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2284. doi:10.1158/1538-7445.AM2015-2284

  • role of lkb1 CRTC1 on glycosylated cox 2 and response to cox 2 inhibition in lung cancer
    Journal of the National Cancer Institute, 2015
    Co-Authors: Min Zhang, Antonio L Amelio, Mohammad Fallahi, Zirong Chen, Yumei Gu, Chengbin Hu, Eric A Welsh, Brienne E Engel
    Abstract:

    Our laboratory isolated CRTC1 (ie, MECT1/TORC1) as the oncogenic element of a recurrent chromosomal rearrangement that underlies the etiology of salivary gland tumors and a rare subset of primary lung tumors (1–4). CRTCs were independently identified as essential LKB1/AMPK family-regulated CREB coactivators that: 1) control a cassette of enzymes linked with glucose/fatty acid metabolism (5–7), 2) mediate the ability of AMPK to regulate aging in C. elegans (8), and 3) are linked in genome-wide association studies to development of esophageal cancer and Barrett’s esophagus (9). LKB1 mutations are among the most common somatic events in lung adenocarcinoma (10,11), and our previous studies detected aberrant CRTC1 activation in lung and esophageal cancer samples carrying LKB1-null alleles (12,13), suggesting a role in lung tumorigenesis. In this model, somatic LKB1 mutations result in hypophosphorylated CRTC1 that is enriched in the nucleus to activate downstream cAMP/CREB target genes that may directly participate in tumorigenesis (see Supplementary Figure 1, available online). In this manuscript, we have now identified CRTC1 activation as a primary event driving the LKB1-null mRNA signature in lung cancer and have detected induction of glycosylated COX-2 (ie, PTSG2) protein, but not the inactive hypoglycosylated species, as a specific biomarker in LKB1-null lung adenocarcinoma resection samples. The related COX-1 and COX-2 products initiate the synthesis of potent lipid signaling messengers called prostaglandins from membrane-bound arachidonic acid using dual cyclooxygenase and peroxidase enzymatic properties (14–16). In contrast to COX-1, the COX-2 product is not detected in most adult normal tissues and is selectively activated by tumor mitogens; elevated levels of COX-2 protein are detected in a large number of premalignant and malignant tissues (17). These observations have focused attention for the past two decades on COX-2 as a tumor biomarker and as a potential therapeutic target for cancer treatment and prevention by COX-2 inhibitors such as aspirin and related nonsteroidal anti-inflammatory agents (NSAIDs) (18). COX-2 inhibitors suppress tumor cell growth in vitro and in vivo by induction of apoptosis (19,20). However, despite promising preclinical results using tumor cell lines in vitro and xenograft mouse models in vivo, there have been inconsistent data supporting COX-2 as a tumor biomarker and as the etiologic target for the cancer prevention activity of aspirin and NSAIDs (21). In this manuscript, we have identified a positive feedback loop between CRTC/COX-2/PGE2/cAMP and have linked LKB1 loss and CRTC1 activation with induction of glycosylated COX-2 protein and preferential sensitivity to COX-2 inhibition. These data suggest a more focused strategy for future cancer treatment and prevention clinical trials.

  • aberrantly activated areg egfr signaling is required for the growth and survival of CRTC1 maml2 fusion positive mucoepidermoid carcinoma cells
    Oncogene, 2014
    Co-Authors: Zirong Chen, Frederic J Kaye, Yumei Gu, Chengbin Hu, Jianliang Li, Huangxuan Shen, Patick K Ha, Janejane Chen, Jing Li, James D Griffin
    Abstract:

    Aberrantly activated AREG–EGFR signaling is required for the growth and survival of CRTC1–MAML2 fusion-positive mucoepidermoid carcinoma cells

  • abstract 3026 targeting aberrantly activated areg egfr signaling in CRTC1 maml2 positive mucoepidermoid carcinoma
    Cancer Research, 2013
    Co-Authors: Zirong Chen, Yumei Gu, Chengbin Hu, Jianliang Li, Jie Chen, Huangxuan Shen, Jiancheng Li, Patick K Ha, Federic J Kaye, James D Griffin
    Abstract:

    Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Salivary gland tumors (SGT) are a group of highly heterogeneous head and neck malignancies with widely varied clinical outcomes and no standard effective treatments. The CRTC1-MAML2 gene fusion, encoded by a recurring chromosomal translocation t(11;19)(q14-21;p12-13), is a highly specific genetic alteration in more than 50% of mucoepidermoid carcinoma (MEC), the most common malignant SGT. In this study, we aimed to define the role of the CRTC1-MAML2 oncogene in the maintenance of MEC tumor growth and to investigate critical downstream target genes and pathways for therapeutic targeting of MEC. By performing gene expression analyses and functional studies via RNA interference and pharmacological modulation, we determined the importance of the CRTC1-MAML2 fusion gene and its downstream AREG-EGFR signaling in human MEC cancer cell growth ad survival in vitro and in vivo using human MEC xenograft models. We found that CRTC1-MAML2 fusion oncogene was required for the growth and survival of fusion-positive human MEC cancer cells in vitro and the in vivo. CRTC1-MAML2 induced the up-regulation of the EGFR ligand AREG by co-activating the transcription factor CREB and AREG subsequently activated EGFR signaling in an autocrine manner that promoted MEC cell growth and survival. Importantly, CRTC1-MAML2-positive MEC cells were highly sensitive to EGFR signaling inhibition. Therefore, our study revealed that aberrantly activated AREG-EGFR signaling is required for CRTC1-MAML2-positive MEC cell growth and survival, suggesting that EGFR-targeted therapies will benefit patients with unresectable CRTC1-MAML2-positive MEC. Citation Format: Zirong Chen, Yumei Gu, Chengbin Hu, Jian-Liang Li, Shuibin Lin, Huangxuan Shen, Chunxia Cao, Jie Chen, Jiancheng Li, Patick K. Ha, Federic J. Kaye, James D. Griffin, Lizi Wu. Targeting aberrantly activated AREG-EGFR signaling in CRTC1-MAML2-positive mucoepidermoid carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3026. doi:10.1158/1538-7445.AM2013-3026