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Fazlul H. Sarkar - One of the best experts on this subject based on the ideXlab platform.
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Functional role of miR-10b in tamoxifen resistance of ER-positive breast cancer cells through down-regulation of HDAC4
BMC cancer, 2015Co-Authors: Aamir Ahmad, Kevin R. Ginnebaugh, Shuping Yin, Aliccia Bollig-fischer, Kaladhar B. Reddy, Fazlul H. SarkarAbstract:For breast cancer patients diagnosed with estrogen receptor (ER)-positive tumors, treatment with tamoxifen is the gold standard. A significant number of patients, however, develop resistance to tamoxifen, and management of such tamoxifen-resistant patients is a major clinical challenge. With an eye to identify novel targets for the treatment of tamoxifen-resistant tumors, we observed that tamoxifen-resistant cells derived from ER-positive MCF-7 cells (MCF7TR) exhibit an increased expression of microRNA-10b (miR-10b). A role of miR-10b in drug-resistance of breast cancer cells has never been investigated, although its is very well known to influence invasion and metastasis.
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Up-regulation of microRNA-10b is associated with the development of breast cancer brain metastasis.
American journal of translational research, 2014Co-Authors: Aamir Ahmad, Seema Sethi, Wei Chen, Rouba Ali-fehmi, Sandeep Mittal, Fazlul H. SarkarAbstract:Brain metastases from primary breast cancer are difficult to treat and associated with poor prognosis. Our understanding of the molecular basis for the development of such cancers is sparse. We hypothesized that the pro-metastatic microRNA-10b (miR-10b) plays a role in breast cancer brain metastasis. The study cohort comprised of twenty patients with breast cancer and brain metastasis as well as ten control patients (age, stage, and follow-up matched) with breast cancer without brain metastasis. All cases were microscopically reviewed to select tumor blocks with >50% tumor cells. RNA was extracted from formalin fixed paraffin embedded (FFPE) tumor tissue blocks. Expression of miR-10b was analyzed using qRT-PCR. The relevance of miR-10b expression was also tested using human breast cancer cell lines. An increased expression of miR-10b was noted in the primary breast cancer specimens of patients who subsequently developed brain metastasis, compared to those who did not. miR-10b also increased the invasive potential of breast cancer cells in vitro. Wilcoxon signed rank test revealed a statistically significant difference between the paired tumors from breast cancers and brain metastasis (p
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up regulation of microRNA 10b is associated with the development of breast cancer brain metastasis
American Journal of Translational Research, 2014Co-Authors: Aamir Ahmad, Seema Sethi, Wei Chen, Sandeep Mittal, Rouba Alifehmi, Fazlul H. SarkarAbstract:Brain metastases from primary breast cancer are difficult to treat and associated with poor prognosis. Our understanding of the molecular basis for the development of such cancers is sparse. We hypothesized that the pro-metastatic microRNA-10b (miR-10b) plays a role in breast cancer brain metastasis. The study cohort comprised of twenty patients with breast cancer and brain metastasis as well as ten control patients (age, stage, and follow-up matched) with breast cancer without brain metastasis. All cases were microscopically reviewed to select tumor blocks with >50% tumor cells. RNA was extracted from formalin fixed paraffin embedded (FFPE) tumor tissue blocks. Expression of miR-10b was analyzed using qRT-PCR. The relevance of miR-10b expression was also tested using human breast cancer cell lines. An increased expression of miR-10b was noted in the primary breast cancer specimens of patients who subsequently developed brain metastasis, compared to those who did not. miR-10b also increased the invasive potential of breast cancer cells in vitro. Wilcoxon signed rank test revealed a statistically significant difference between the paired tumors from breast cancers and brain metastasis (p <0.001). Increased expression of miR-10b appears to be associated with breast cancer brain metastasis. These findings are clinically relevant since miR-10b could serve as a prognostic and/or therapeutic target for anti-metastatic therapy. Identifying molecular signatures of primary breast cancers which have a propensity for brain metastasis is critical for designing novel therapies to counter the development of brain metastasis in patients diagnosed with breast cancer.
Murray Korc - One of the best experts on this subject based on the ideXlab platform.
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a microRNA signature in circulating exosomes is superior to exosomal glypican 1 levels for diagnosing pancreatic cancer
Cancer Letters, 2017Co-Authors: Xianyin Lai, Mu Wang, Samantha Deitz Mcelyea, Stuart Sherman, Michael G House, Murray KorcAbstract:Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy that often presents clinically at an advanced stage and that may be confused with chronic pancreatitis (CP). Conversely, CP may be misdiagnosed as PDAC leading to unwarranted pancreas resection. Therefore, early PDAC diagnosis and clear differentiation between PDAC and CP are crucial for improved care. Exosomes are circulating microvesicles whose components can serve as cancer biomarkers. We compared exosomal glypican-1 (GPC1) and microRNA levels in normal control subjects and in patients with PDAC and CP. We report that exosomal GPC1 is not diagnostic for PDAC, whereas high exosomal levels of microRNA-10b, (miR-10b), miR-21, miR-30c, and miR-181a and low miR-let7a readily differentiate PDAC from normal control and CP samples. By contrast with GPC1, elevated exosomal miR levels decreased to normal values within 24 h following PDAC resection. All 29 PDAC cases exhibited significantly elevated exosomal miR-10b and miR-30c levels, whereas 8 cases had normal or slightly increased CA 19-9 levels. Thus, our exosomal miR signature is superior to exosomal GPC1 or plasma CA 19-9 levels in establishing a diagnosis of PDAC and differentiating between PDAC and CP.
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label free nanoplasmonic based short noncoding rna sensing at attomolar concentrations allows for quantitative and highly specific assay of microRNA 10b in biological fluids and circulating exosomes
ACS Nano, 2015Co-Authors: Gayatri K Joshi, Samantha Deitzmcelyea, Thakshila Liyanage, Katie N Lawrence, Sonali Mali, Rajesh Sardar, Murray KorcAbstract:microRNAs are short noncoding RNAs consisting of 18-25 nucleotides that target specific mRNA moieties for translational repression or degradation, thereby modulating numerous biological processes. Although microRNAs have the ability to behave like oncogenes or tumor suppressors in a cell-autonomous manner, their exact roles following release into the circulation are only now being unraveled and it is important to establish sensitive assays to measure their levels in different compartments in the circulation. Here, an ultrasensitive localized surface plasmon resonance (LSPR)-based microRNA sensor with single nucleotide specificity was developed using chemically synthesized gold nanoprisms attached onto a solid substrate with unprecedented long-term stability and reversibility. The sensor was used to specifically detect microRNA-10b at the attomolar (10(-18) M) concentration in pancreatic cancer cell lines, derived tissue culture media, human plasma, and media and plasma exosomes. In addition, for the first time, our label-free and nondestructive sensing technique was used to quantify microRNA-10b in highly purified exosomes isolated from patients with pancreatic cancer or chronic pancreatitis, and from normal controls. We show that microRNA-10b levels were significantly higher in plasma-derived exosomes from pancreatic ductal adenocarcinoma patients when compared with patients with chronic pancreatitis or normal controls. Our findings suggest that this unique technique can be used to design novel diagnostic strategies for pancreatic and other cancers based on the direct quantitative measurement of plasma and exosome microRNAs, and can be readily extended to other diseases with identifiable microRNA signatures.
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microRNA-10b enhances pancreatic cancer cell invasion by suppressing TIP30 expression and promoting EGF and TGF-β actions.
Oncogene, 2013Co-Authors: H. Ouyang, Jesse Gore, S. Deitz, Murray KorcAbstract:Increased microRNA-10b (miR-10b) expression in the cancer cells in pancreatic ductal adenocarcinoma (PDAC) is a marker of disease aggressiveness. In the present study, we determined that plasma miR-10b levels are significantly increased in PDAC patients by comparison with normal controls. By gene profiling, we identified potential targets downregulated by miR-10b, including Tat-interacting protein 30 (TIP30). Immunoblotting and luciferase reporter assays confirmed that TIP30 was a direct miR-10b target. Downregulation of TIP30 by miR-10b or siRNA-mediated silencing of TIP30 enhanced epidermal growth factor (EGF)-dependent invasion. The actions of miR-10b were abrogated by expressing a modified TIP30 cDNA resistant to miR-10b. EGF-induced EGF receptor (EGFR) tyrosine phosphorylation and extracellular signal–regulated kinase phosphorylation were enhanced by miR-10b, and these effects were mimicked by TIP30 silencing. The actions of EGF in the presence of miR-10b were blocked by EGFR kinase inhibition with erlotinib and by dual inhibition of PI3K (phosphatidylinositol 3′-kinase) and MEK. Moreover, miR-10b, EGF and transforming growth factor-beta (TGF-β) combined to markedly increase cell invasion, and this effect was blocked by the combination of erlotinib and SB505124, a type I TGF-β receptor inhibitor. miR-10b also enhanced the stimulatory effects of EGF and TGF-β on cell migration and epithelial–mesenchymal transition (EMT) and decreased the expression of RAP2A, EPHB2, KLF4 and NF1. Moreover, miR-10b overexpression accelerated pancreatic cancer cell (PCC) proliferation and tumor growth in an orthotopic model. Thus, plasma miR-10b levels may serve as a diagnostic marker in PDAC, whereas intra-tumoral miR-10b promotes PCC proliferation and invasion by suppressing TIP30, which enhances EGFR signaling, facilitates EGF–TGF-β cross-talk and enhances the expression of EMT-promoting genes, whereas decreasing the expression of several metastasis-suppressing genes. Therefore, therapeutic targeting of miR-10b in PDAC may interrupt growth-promoting deleterious EGF–TGF-β interactions and antagonize the metastatic process at various levels.
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microRNA-10b Expression Correlates with Response to Neoadjuvant Therapy and Survival in Pancreatic Ductal Adenocarcinoma
Clinical cancer research : an official journal of the American Association for Cancer Research, 2011Co-Authors: Meir Preis, Timothy B. Gardner, Stuart R. Gordon, J. Marc Pipas, Todd A. Mackenzie, Erin E. Klein, Daniel S. Longnecker, Edward J. Gutmann, Lorenzo F. Sempere, Murray KorcAbstract:Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Diagnosis and management of PDAC are hampered by the absence of sensitive and specific disease biomarkers. microRNAs (miRNA) are noncoding regulatory RNAs involved in initiation and progression of human cancers. In this study, we sought to determine whether miR-10b could serve as a biomarker for PDAC. Experimental Design: miRNA expression was characterized by fluorescence-based in situ hybridization using locked nucleic acid–modified DNA probes against miR-10b, miR-21, miR-155, miR-196a, and miR-210, followed by codetection of proteins by immunohistochemistry on the same tissue sections. miRNA expression in surgically resected PDAC tissues and in endoscopic ultrasonography (EUS)-guided fine-needle aspirate (EUS-FNA) samples was analyzed in cytokeratin 19 (CK19)–positive epithelial cells using optical intensity analysis. Results: In 10 resected PDAC samples, miR-10b was the most frequently and consistently overexpressed miRNA among characterized miRNAs, exhibiting a four-fold increase in the cancer cells ( P = 0.012). Given this preferential overexpression of miR-10b, we sought to determine whether miR-10b expression was clinically relevant. Accordingly, miR-10b expression was examined in 106 EUS-FNA samples obtained from pancreatic lesions. miR-10b expression was increased in cancer cells compared with CK19-positive epithelial cells in benign lesions ( P = 0.0001). In patients with PDACs, lower levels of miR-10b were associated with improved response to multimodality neoadjuvant therapy, likelihood of surgical resection, delayed time to metastasis, and increased survival. Conclusion: miR-10b is a novel diagnostic biomarker for PDACs when assessing pancreatic lesions. Expression of miR-10b is predictive of response to neoadjuvant therapy and outcome in this disease. Clin Cancer Res; 17(17); 5812–21. ©2011 AACR .
Aamir Ahmad - One of the best experts on this subject based on the ideXlab platform.
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Functional role of miR-10b in tamoxifen resistance of ER-positive breast cancer cells through down-regulation of HDAC4
BMC cancer, 2015Co-Authors: Aamir Ahmad, Kevin R. Ginnebaugh, Shuping Yin, Aliccia Bollig-fischer, Kaladhar B. Reddy, Fazlul H. SarkarAbstract:For breast cancer patients diagnosed with estrogen receptor (ER)-positive tumors, treatment with tamoxifen is the gold standard. A significant number of patients, however, develop resistance to tamoxifen, and management of such tamoxifen-resistant patients is a major clinical challenge. With an eye to identify novel targets for the treatment of tamoxifen-resistant tumors, we observed that tamoxifen-resistant cells derived from ER-positive MCF-7 cells (MCF7TR) exhibit an increased expression of microRNA-10b (miR-10b). A role of miR-10b in drug-resistance of breast cancer cells has never been investigated, although its is very well known to influence invasion and metastasis.
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Up-regulation of microRNA-10b is associated with the development of breast cancer brain metastasis.
American journal of translational research, 2014Co-Authors: Aamir Ahmad, Seema Sethi, Wei Chen, Rouba Ali-fehmi, Sandeep Mittal, Fazlul H. SarkarAbstract:Brain metastases from primary breast cancer are difficult to treat and associated with poor prognosis. Our understanding of the molecular basis for the development of such cancers is sparse. We hypothesized that the pro-metastatic microRNA-10b (miR-10b) plays a role in breast cancer brain metastasis. The study cohort comprised of twenty patients with breast cancer and brain metastasis as well as ten control patients (age, stage, and follow-up matched) with breast cancer without brain metastasis. All cases were microscopically reviewed to select tumor blocks with >50% tumor cells. RNA was extracted from formalin fixed paraffin embedded (FFPE) tumor tissue blocks. Expression of miR-10b was analyzed using qRT-PCR. The relevance of miR-10b expression was also tested using human breast cancer cell lines. An increased expression of miR-10b was noted in the primary breast cancer specimens of patients who subsequently developed brain metastasis, compared to those who did not. miR-10b also increased the invasive potential of breast cancer cells in vitro. Wilcoxon signed rank test revealed a statistically significant difference between the paired tumors from breast cancers and brain metastasis (p
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up regulation of microRNA 10b is associated with the development of breast cancer brain metastasis
American Journal of Translational Research, 2014Co-Authors: Aamir Ahmad, Seema Sethi, Wei Chen, Sandeep Mittal, Rouba Alifehmi, Fazlul H. SarkarAbstract:Brain metastases from primary breast cancer are difficult to treat and associated with poor prognosis. Our understanding of the molecular basis for the development of such cancers is sparse. We hypothesized that the pro-metastatic microRNA-10b (miR-10b) plays a role in breast cancer brain metastasis. The study cohort comprised of twenty patients with breast cancer and brain metastasis as well as ten control patients (age, stage, and follow-up matched) with breast cancer without brain metastasis. All cases were microscopically reviewed to select tumor blocks with >50% tumor cells. RNA was extracted from formalin fixed paraffin embedded (FFPE) tumor tissue blocks. Expression of miR-10b was analyzed using qRT-PCR. The relevance of miR-10b expression was also tested using human breast cancer cell lines. An increased expression of miR-10b was noted in the primary breast cancer specimens of patients who subsequently developed brain metastasis, compared to those who did not. miR-10b also increased the invasive potential of breast cancer cells in vitro. Wilcoxon signed rank test revealed a statistically significant difference between the paired tumors from breast cancers and brain metastasis (p <0.001). Increased expression of miR-10b appears to be associated with breast cancer brain metastasis. These findings are clinically relevant since miR-10b could serve as a prognostic and/or therapeutic target for anti-metastatic therapy. Identifying molecular signatures of primary breast cancers which have a propensity for brain metastasis is critical for designing novel therapies to counter the development of brain metastasis in patients diagnosed with breast cancer.
Sushanta K. Banerjee - One of the best experts on this subject based on the ideXlab platform.
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Abstract 2053: Regulation of microRNA-10b byCCN5/WISP-2in breast cancer: A novel mechanism ofCCN5/WISP-2mediated suppression of invasive front
Cellular and Molecular Biology, 2010Co-Authors: Inamul Haque, Snigdha Banerjee, Smita Mehta, Teresa A. Phillips, Gopal Dhar, Suman Kambhampati, Sushanta K. BanerjeeAbstract:Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Metastatic cells are a subset of primary tumor cells that have the skill to complete multi-step metastatic cascades, including dissemination, migration, extravasation, and eventual proliferation) at a discontinuous secondary site. Understanding the molecular biology of cancer metastasis may provide novel intervention strategies to control metastatic lesions, and/or to improve the quality of life for the patients with these advanced diseases. MicoRNAs are naturally occurring single-stranded RNA molecules that posttranscriptionally regulate the expression of target mRNA transcripts. Many of these target mRNA transcripts are involved in cell proliferation, differentiation and apoptosis, processes commonly altered during tumorigenesis. Recent findings have shown that microRNA-10b (miR-10b) is highly expressed in metastatic breast cancer cells and positively regulates cell migration and invasion. Expression of miR-10b is induced by Twist, a transcription factor that binds to putative promoter of miR-10b. We hypothesized that whether nullification of CCN5/WISP-2, an antiinvasive gene has any role in miR-10b expression. We found that nullification of CCN5/WISP-2 in ER-positive noninvasive breast tumor cell upregulates the miR-10b expression. Interestingly, we also found the upregulation of Twist by silencing CCN5/WISP-2. Collectively, we conclude that CCN5/WISP-2 may be a critical regulator of miR-10b expression through the HIF-1α-Twist signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2053.
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abstract 2053 regulation of microRNA 10b byccn5 wisp 2in breast cancer a novel mechanism ofccn5 wisp 2mediated suppression of invasive front
Cancer Research, 2010Co-Authors: Inamul Haque, Snigdha Banerjee, Smita Mehta, Teresa A. Phillips, Gopal Dhar, Suman Kambhampati, Sushanta K. BanerjeeAbstract:Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Metastatic cells are a subset of primary tumor cells that have the skill to complete multi-step metastatic cascades, including dissemination, migration, extravasation, and eventual proliferation) at a discontinuous secondary site. Understanding the molecular biology of cancer metastasis may provide novel intervention strategies to control metastatic lesions, and/or to improve the quality of life for the patients with these advanced diseases. MicoRNAs are naturally occurring single-stranded RNA molecules that posttranscriptionally regulate the expression of target mRNA transcripts. Many of these target mRNA transcripts are involved in cell proliferation, differentiation and apoptosis, processes commonly altered during tumorigenesis. Recent findings have shown that microRNA-10b (miR-10b) is highly expressed in metastatic breast cancer cells and positively regulates cell migration and invasion. Expression of miR-10b is induced by Twist, a transcription factor that binds to putative promoter of miR-10b. We hypothesized that whether nullification of CCN5/WISP-2, an antiinvasive gene has any role in miR-10b expression. We found that nullification of CCN5/WISP-2 in ER-positive noninvasive breast tumor cell upregulates the miR-10b expression. Interestingly, we also found the upregulation of Twist by silencing CCN5/WISP-2. Collectively, we conclude that CCN5/WISP-2 may be a critical regulator of miR-10b expression through the HIF-1α-Twist signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2053.
Nadiya M. Teplyuk - One of the best experts on this subject based on the ideXlab platform.
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therapeutic potential of targeting microRNA 10b in established intracranial glioblastoma first steps toward the clinic
Embo Molecular Medicine, 2016Co-Authors: Nadiya M. Teplyuk, Galina Gabriely, Erik J. Uhlmann, Natalia Volfovsky, Yang Wang, Jian Teng, Priya Karmali, Eric G Marcusson, Merlene Peter, Athul MohanAbstract:Abstract microRNA‐10b (miR‐10b) is a unique oncogenic miRNA that is highly expressed in all GBM subtypes, while absent in normal neuroglial cells of the brain. miR‐10b inhibition strongly impairs proliferation and survival of cultured glioma cells, including glioma‐initiating stem‐like cells (GSC). Although several miR‐10b targets have been identified previously, the common mechanism conferring the miR‐10b‐sustained viability of GSC is unknown. Here, we demonstrate that in heterogeneous GSC, miR‐10b regulates cell cycle and alternative splicing, often through the non‐canonical targeting via 5′UTRs of its target genes, including MBNL1‐3, SART3, and RSRC1. We have further assessed the inhibition of miR‐10b in intracranial human GSC‐derived xenograft and murine GL261 allograft models in athymic and immunocompetent mice. Three delivery routes for the miR‐10b antisense oligonucleotide inhibitors (ASO), direct intratumoral injections, continuous osmotic delivery, and systemic intravenous injections, have been explored. In all cases, the treatment with miR‐10b ASO led to targets’ derepression, and attenuated growth and progression of established intracranial GBM. No significant systemic toxicity was observed upon ASO administration by local or systemic routes. Our results indicate that miR‐10b is a promising candidate for the development of targeted therapies against all GBM subtypes.
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Therapeutic potential of targeting microRNA‐10b in established intracranial glioblastoma: first steps toward the clinic
EMBO molecular medicine, 2016Co-Authors: Nadiya M. Teplyuk, Galina Gabriely, Erik J. Uhlmann, Natalia Volfovsky, Yang Wang, Jian Teng, Priya Karmali, Eric G Marcusson, Merlene Peter, Athul MohanAbstract:microRNA-10b (miR-10b) is a unique oncogenic miRNA that is highly expressed in all GBM subtypes, while absent in normal neuroglial cells of the brain. miR-10b inhibition strongly impairs proliferation and survival of cultured glioma cells, including glioma-initiating stem-like cells (GSC). Although several miR-10b targets have been identified previously, the common mechanism conferring the miR-10b-sustained viability of GSC is unknown. Here, we demonstrate that in heterogeneous GSC, miR-10b regulates cell cycle and alternative splicing, often through the non-canonical targeting via 5'UTRs of its target genes, including MBNL1-3, SART3, and RSRC1. We have further assessed the inhibition of miR-10b in intracranial human GSC-derived xenograft and murine GL261 allograft models in athymic and immunocompetent mice. Three delivery routes for the miR-10b antisense oligonucleotide inhibitors (ASO), direct intratumoral injections, continuous osmotic delivery, and systemic intravenous injections, have been explored. In all cases, the treatment with miR-10b ASO led to targets' derepression, and attenuated growth and progression of established intracranial GBM. No significant systemic toxicity was observed upon ASO administration by local or systemic routes. Our results indicate that miR-10b is a promising candidate for the development of targeted therapies against all GBM subtypes.
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microRNA 10b inhibition reduces e2f1 mediated transcription and mir 15 16 activity in glioblastoma
Oncotarget, 2015Co-Authors: Nadiya M. Teplyuk, Galina Gabriely, Erik J. Uhlmann, Yang Wang, Priya Karmali, Andus Hon-kit Wong, Meenakshi Basu, Anant Jain, Antonio E Chiocca, Robert M. StephensAbstract:microRNA-10b (miR-10b) is commonly elevated in glioblastoma (GBM), while not expressed in normal brain tissues. Targeted inhibition of miR-10b has pleiotropic effects on GBM derived cell lines, it reduces GBM growth in animal models, but does not affect normal neurons and astrocytes. This data raises the possibility of developing miR-10b-targeting GBM therapy. However, the mechanisms contributing to miR-10b-mediated glioma cell survival and proliferation are unexplored. We found that inhibition of miR-10b has distinct effects on specific glioma cell lines. In cells expressing high levels of tumor suppressor p21WAF1/Cip1, it represses E2F1-mediated transcription, leading to down-regulation of multiple E2F1 target genes encoding for S-phase specific proteins, epigenetic modulators, and miRNAs (e.g. miR-15/16), and thereby stalling progression through the S-phase of cell cycle. Subsequently, miR-15/16 activities are reduced and many of their direct targets are de-repressed, including ubiquitin ligase FBXW7 that destabilizes Cyclin E. Conversely, GBM cells expressing low p21 level, or after p21 knock-down, exhibit weaker or no E2F1 response to miR-10b inhibition. Comparative analysis of The Cancer Genome Atlas revealed a strong correlation between miR-10b and multiple E2F target genes in GBM and low-grade glioma. Taken together, these findings indicate that miR-10b regulates E2F1-mediated transcription in GBM, in a p21-dependent fashion.
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microRNA-10b inhibition reduces E2F1-mediated transcription and miR-15/16 activity in glioblastoma
Oncotarget, 2015Co-Authors: Nadiya M. Teplyuk, Galina Gabriely, Erik J. Uhlmann, Yang Wang, Priya Karmali, Andus Hon-kit Wong, Meenakshi Basu, Anant Jain, E. Antonio Chiocca, Robert M. StephensAbstract:microRNA-10b (miR-10b) is commonly elevated in glioblastoma (GBM), while not expressed in normal brain tissues. Targeted inhibition of miR-10b has pleiotropic effects on GBM derived cell lines, it reduces GBM growth in animal models, but does not affect normal neurons and astrocytes. This data raises the possibility of developing miR-10b-targeting GBM therapy. However, the mechanisms contributing to miR-10b-mediated glioma cell survival and proliferation are unexplored. We found that inhibition of miR-10b has distinct effects on specific glioma cell lines. In cells expressing high levels of tumor suppressor p21WAF1/Cip1, it represses E2F1-mediated transcription, leading to down-regulation of multiple E2F1 target genes encoding for S-phase specific proteins, epigenetic modulators, and miRNAs (e.g. miR-15/16), and thereby stalling progression through the S-phase of cell cycle. Subsequently, miR-15/16 activities are reduced and many of their direct targets are de-repressed, including ubiquitin ligase FBXW7 that destabilizes Cyclin E. Conversely, GBM cells expressing low p21 level, or after p21 knock-down, exhibit weaker or no E2F1 response to miR-10b inhibition. Comparative analysis of The Cancer Genome Atlas revealed a strong correlation between miR-10b and multiple E2F target genes in GBM and low-grade glioma. Taken together, these findings indicate that miR-10b regulates E2F1-mediated transcription in GBM, in a p21-dependent fashion.
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Context effect: microRNA-10b in cancer cell proliferation, spread and death.
Autophagy, 2011Co-Authors: Galina Gabriely, Nadiya M. Teplyuk, Anna M. KrichevskyAbstract:Single microRNA (miRNA) can regulate expression of several or multiple principal targets in a specific microenvironment. In different cellular contexts, the same miRNA may exhibit diverse functions, depending on the repertoire and stoichiometry of its direct mRNA targets. For instance, in breast cancer, microRNA-10b (miR-10b) promotes invasion and metastasis of tumor cells through post-transcriptional regulation of HOXD10. In contrast, in glioblastoma (GBM), the most common and malignant primary brain tumor, miR-10b promotes proliferation and prevents death of cancer cells by targeting cell cycle inhibitors and pro-apoptotic genes. Here, we discuss a unique role of miR-10b in cancer cell survival, in diverse tumor microenvironments.