The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Frank J Slack - One of the best experts on this subject based on the ideXlab platform.
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tumor penetrating nanomedicine targeting both an Oncomir and an oncogene in pancreatic cancer
Oncotarget, 2019Co-Authors: Maudemmanuelle Gilles, Liangliang Hao, Kaelyn Brown, Jihoon Lim, Sangeeta N Bhatia, Frank J SlackAbstract:Developing new targeted therapy for pancreatic cancer is one of the major current challenges in cancer research. KRAS mutations and miRNA dysregulation (e.g. miR-21-5p Oncomir) play key roles in Pancreatic Ductal Adenocarcinoma (PDAC), leading to rapid progression of the disease. As the KRAS mutation is a main driver of PDAC, anti-KRAS strategies remain a major therapeutic approach for PDAC treatment. Previously, utilization of either siKRAS or small chemically modified single-stranded RNA molecules that specifically disable miR-21 (anti-miR-21) were effective in slowing PDAC tumor growth in various tumor models when packaged in an innovative delivery system (TPN) required for efficient drug delivery to the PDAC tumor site. Here we have tested the utility of targeting the KRAS pathway through multiple mechanisms and via dual targeting of a PDAC Oncomir and oncogene. Initially we found that miR-217, which has been shown to directly regulate KRAS expression, is downregulated in our PDAC samples, thus we tested the benefits of anti-miR-21, miR-217 mimic or siKRAS loaded into the tumor-penetrating nanoparticles (TPN) that we had previously shown to potently target the largely impenetrable PDAC tumors, and found an enhanced anti-tumoral response upon dual treatments in KRAS-mutated PDAC models.
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Oncomir or tumor suppressor the duplicity of micrornas in cancer
Cancer Research, 2016Co-Authors: Alexander A Svoronos, Donald M Engelman, Frank J SlackAbstract:MicroRNAs (miRNA) are short, noncoding RNAs whose dysregulation has been implicated in most, if not all, cancers. They regulate gene expression by suppressing mRNA translation and reducing mRNA stability. To this end, there is a great deal of interest in modifying miRNA expression levels for the treatment of cancer. However, the literature is fraught with inconsistent accounts as to whether various miRNAs are oncogenic or tumor suppressive. In this review, we directly examine these inconsistencies and propose several mechanisms to explain them. These mechanisms include the possibility that specific miRNAs can simultaneously produce competing oncogenic and tumor suppressive effects by suppressing both tumor suppressive mRNAs and oncogenic mRNAs, respectively. In addition, miRNAs can modulate tumor-modifying extrinsic factors, such as cancer-immune system interactions, stromal cell interactions, oncoviruses, and sensitivity to therapy. Ultimately, it is the balance between these processes that determines whether a specific miRNA produces a net oncogenic or net tumor suppressive effect. A solid understanding of this phenomenon will likely prove valuable in evaluating miRNA targets for cancer therapy. Cancer Res; 76(13); 3666-70. ©2016 AACR.
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abstract 974 targeting the tumor microenvironment with antimirs that exploit Oncomir addiction in lymphoma
Cancer Research, 2014Co-Authors: Christopher J Cheng, Donald M Engelman, Mark Saltzman, Frank J SlackAbstract:Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA The purpose of this study was to develop a tumor-targeted therapeutic to antagonize aberrantly expressed microRNAs in lymphoma. MicroRNA dysfunction has been linked to the onset cancer. For example, in lymphoma miR-155 can affect carcinogenesis by acting as a hyperexpressed microRNA oncogene, or Oncomir. As ubiquitous regulators of gene expression, microRNAs are promising therapeutic targets. As such, numerous recent preclinical and clinical studies have utilized therapeutic oligonucleotides, known as antimiRs, to bind to and inhibit disease-associated microRNAs. However, the efficacy of systemically administered antimiRs is hindered by non-specific tissue targeting, which typically results in substantial liver uptake. We have developed an antimiR-peptide conjugate which preferentially targets the acidic tumor microenvironment. Intravital imaging and confocal tissue analysis show that this conjugate accumulates in tumors, while avoiding the liver, and has no observable systemic or cellular toxicity. The antimiR component of this conjugate comprises charge-neutral peptide nucleic acids (PNA). Due to their stability and high binding affinity, PNAs are effective antimiRs; however, they do not efficiently enter cells without a delivery vector. In addition to its tumor targeting benefits, we have previously shown that this peptide can deliver cargo into cells by translocating tethered molecules directly across lipid membranes. Via this non-endocytic mechanism, this peptide also promotes the effective delivery of PNA antimiRs into cultured B lymphocytes. Therefore, this conjugate both targets tumors and delivers antimiRs into cells via non-canonical pathways. Here we will detail the design and characterization of this conjugate, with specific emphasis on its ability to deliver antimiRs into cells via a non-endocytic route. In cultured cells we will demonstrate the efficacy of miR-155 inhibition using reporter and cell viability assays. For in vivo studies, we developed a metastatic mouse model of inducible diffuse large B cell lymphoma that is addicted to miR-155, such that lymphomagenesis is dependent on overexpression of the Oncomir, and withdrawal of miR-155 leads to cancer regression. Using this spontaneous miR-155-addicted lymphoma tumor model, we will discuss the biodistribution of the conjugate, as well as the effects of antimiR-155 therapy on lymphoid tumor growth and metastasis. In addition, we will outline how antagonizing miR-155 affects novel gene targets and biological pathways involved in Oncomir addiction, which were uncovered via RNA-seq differential gene expression analysis. Oncomirs have recently established a new paradigm for anti-cancer gene therapy. This work introduces a versatile and non-toxic tumor microenvironment-targeted system that exploits these lynchpin molecules as therapeutic tools. Citation Format: Christopher J. Cheng, Don M. Engelman, Mark Saltzman, Frank J. Slack. Targeting the tumor microenvironment with antimiRs that exploit Oncomir addiction in lymphoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 974. doi:10.1158/1538-7445.AM2014-974
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the duality of Oncomir addiction in the maintenance and treatment of cancer
Cancer Journal, 2012Co-Authors: Christopher J Cheng, Frank J SlackAbstract:It has long been established that cancers can become addicted to particular oncogenes. Despite the genetic complexity that governs tumorigenesis, certain cancers can exhibit a critical dependency on the expression of a single oncogene, which when removed leads to death of the cancer cell. Recent observations on the relationships between regulatory RNAs and cancer have revealed that this concept of oncogene addiction extends to microRNAs (miRNAs) as well. Certain cancers exhibit a dependency on the expression of a single oncogenic miRNA, or Oncomir. The field of miRNA biology and its involvement in diseases such as cancer has seen tremendous advances over the past decade. However, little is known about the phenomenon of Oncomir addiction. In this review, we introduce the concept of proto-Oncomirs, or miRNAs that gain oncogenic activity after an initiating event. Further, by highlighting the role of proto-Oncomirs in generating malignant phenotypes, we glean possible insights into the mechanisms that guide Oncomir addiction. Additionally, toward the realization of genetically-driven personalized medicine, some of the most clinically successful anticancer strategies have involved targeting addictive oncogenes such as HER2, BCR/ABL, EGFR, and VEGF. Elucidating how addictive miRNAs can perpetuate cancer may reveal additional critical molecular targets to exploit for therapeutic purposes. Therefore, in this review, we also summarize the field of anti-miRNA therapeutics, in which antisense and nanoscale delivery technologies are the driving force. Addictive Oncomirs are a double-edged sword; addicted cancers are dependent on Oncomirs that are highly potent therapeutic targets. Dissection of this phenomenon may reveal the mechanisms through which lynchpin miRNAs can perpetuate cancer and present a new paradigm for miRNA-based cancer therapy.
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Oncomir addiction in an in vivo model of microrna 21 induced pre b cell lymphoma
Nature, 2010Co-Authors: Pedro P Medina, Mona Nolde, Frank J SlackAbstract:MicroRNAs (miRNAs) — small RNA molecules that regulate gene expression and have an important role in establishing cell identity — have been linked to human cancers, where they are referred to as Oncomirs. One model of cancer development proposes that proliferating cells become 'addicted' to activating mutations in an oncogene, and it has been suggested that tumours may also become dependent on Oncomirs. Work in mice that were engineered to conditionally express microRNA-21 (miR-21), which is overexpressed in most tumour types so far analysed, now shows that miR-21 induces pre-B-cell lymphoma. In the absence of miR-21, malignant cells undergo apoptosis and regress, as would be expected if they were addicted to its presence. The pharmacological inactivation of 'Oncomir-21' and other similar miRNAs may therefore be of therapeutic benefit. One model for cancer development posits that the proliferating cells in a tumour can become 'addicted' to activating mutations in an oncogene. With the realization that certain microRNAs promote tumorigenesis, it has been proposed that tumours may also become dependent on such 'Oncomirs'. Here, evidence is provided that the gene encoding microRNA-21 is an oncogene, and that in its absence, tumours undergo apoptosis and regress. Thus tumours can indeed become addicted to Oncomirs. MicroRNAs (miRNAs) belong to a recently discovered class of small RNA molecules that regulate gene expression at the post-transcriptional level. miRNAs have crucial functions in the development and establishment of cell identity, and aberrant metabolism or expression of miRNAs has been linked to human diseases, including cancer1. Components of the miRNA machinery and miRNAs themselves are involved in many cellular processes that are altered in cancer, such as differentiation, proliferation and apoptosis. Some miRNAs, referred to as Oncomirs2, show differential expression levels in cancer and are able to affect cellular transformation, carcinogenesis and metastasis, acting either as oncogenes or tumour suppressors. The phenomenon of ‘oncogene addiction’ reveals that despite the multistep nature of tumorigenesis, targeting of certain single oncogenes can have therapeutic value3,4, and the possibility of Oncomir addiction has been proposed but never demonstrated3. MicroRNA-21 (miR-21) is a unique miRNA in that it is overexpressed in most tumour types analysed so far. Despite great interest in miR-21, most of the data implicating it in cancer have been obtained through miRNA profiling and limited in vitro functional assays. To explore the role of miR-21 in cancer in vivo, we used Cre and Tet-off technologies to generate mice conditionally expressing miR-21. Here we show that overexpression of miR-21 leads to a pre-B malignant lymphoid-like phenotype, demonstrating that mir-21 is a genuine oncogene. When miR-21 was inactivated, the tumours regressed completely in a few days, partly as a result of apoptosis. These results demonstrate that tumours can become addicted to Oncomirs and support efforts to treat human cancers through pharmacological inactivation of miRNAs such as miR-21.
Jenny T Mao - One of the best experts on this subject based on the ideXlab platform.
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grape seed procyanidin extract against lung cancer the role of microrna 106b bioavailability and bioactivity
Oncotarget, 2018Co-Authors: Bingye Xue, Larry Massie, Clifford Qualls, Jenny T MaoAbstract:// Bingye Xue 1 , Qing-Yi Lu 2 , Larry Massie 3 , Clifford Qualls 4 and Jenny T. Mao 1 1 Pulmonary, Critical Care, and Sleep Section, New Mexico Veterans Administration Health Care System, University of New Mexico, Biomedical Research Institute of New Mexico, Albuquerque, NM, USA 2 UCLA Center for Human Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA 3 Pathology and Clinical Laboratory Services, New Mexico Veterans Administration Health Care System, University of New Mexico, Albuquerque, NM, USA 4 Biomedical Research Institute of New Mexico, New Mexico Veterans Administration Health Care System, University of New Mexico, Albuquerque, NM, USA Correspondence to: Jenny T. Mao, email: jenny.mao@va.gov Keywords: Oncomir; P21; CDKN1A; pharmacokinetics; pharmacodynamics Received: July 23, 2017 Accepted: February 10, 2018 Epub: February 16, 2018 Published: March 20, 2018 ABSTRACT MiR-106b is an Oncomir and a potential target for anti-cancer therapy. We hypothesize that grape seed procyanidin extract (GSE) exerts antineoplastic effects on lung cancer through modulations of miR-106b and its downstream target. We found that GSE significantly down-regulated miR-106b in a variety of lung neoplastic cells and increased cyclin-dependent kinase inhibitor 1A ( CDKN1A ) mRNA and protein (p21) levels. Transfection of miR-106b mimics reversed the up-regulations of CDKN1A mRNA and p21, abrogated the GSE induced anti-proliferative and anti-invasive properties in lung cancer cells. Oral gavage of leucoselect phytosome (LP), a standardized GSE to athymic nude mice down-regulated MIR106B mRNA and miR-106b expressions, and increased CDKN1A mRNA expression in tumor xenografts, correlating to significant reduction of tumor growth. To assess bioavailability, GSE and metabolites in plasma levels, between 60–90 minutes after gavage of LP were measured by LC/MS at treatment week 4 and 8. A novel bioactivity assay was also developed using lung homogenates from treated mice co-cultured with human lung cancer cells. LP-treated mouse lung homogenates significantly reduced proliferations of various lung cancer cells. Our findings reveal novel antineoplastic mechanisms by GSE, further define the pharmacokinetics and pharmacodynamics of LP, and support the continued investigation of LP against lung cancer.
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microrna 19a b mediates grape seed procyanidin extract induced anti neoplastic effects against lung cancer
Journal of Nutritional Biochemistry, 2016Co-Authors: Jenny T Mao, Bingye Xue, Jane Smoake, Heesung Park, Susanne M Henning, Windie Burns, Alvise Bernabei, David Elashoff, Kenneth J Serio, Larry MassieAbstract:Abstract Oncomirs are microRNAs (miRNA) associated with carcinogenesis and malignant transformation. They have emerged as potential molecular targets for anti-cancer therapy. We hypothesize that grape seed procyanidin extract (GSE) exerts antineoplastic effects through modulations of Oncomirs and their downstream targets. We found that GSE significantly down-regulated Oncomirs miR-19a and -19b in a variety of lung neoplastic cells. GSE also increased mRNA and protein levels of insulin-like growth factor II receptor (IGF-2R) and phosphatase and tensin homolog (PTEN), both predicted targets of miR-19a and -19b. Furthermore, GSE significantly increased PTEN activity and decreased AKT phosphorylation in A549 cells. Transfection of miR-19a and -19b mimics reversed the up-regulations of IGF2R and PTEN gene expression and abrogated the GSE induced anti-proliferative response. Additionally, oral administration of leucoselect phytosome, comprised of standardized grape seed oligomeric procyanidins complexed with soy phospholipids, to athymic nude mice via gavage, significantly down-regulated miR-19a, -19b and the miR-17-92 cluster host gene (MIR17HG) expressions, increased IGF-2R, PTEN, decreased phosphorylated-AKT in A549 xenograft tumors, and markedly inhibited tumor growth. To confirm the absorption of orally administered GSE, plasma procyanidin B1 levels, between 60 and 90 min after gavage of leucoselect phytosome (400 mg/kg), were measured by LC/MS at week 2 and 8 of treatment; the estimated concentration that was associated with 50% growth inhibition (IC 50 ) (1.3 μg/mL) in vitro was much higher than the IC 50 (0.032–0.13 μg/ml) observed in vivo . Our findings reveal novel antineoplastic mechanisms by GSE and support the clinical translation of leucoselect phytosome as an anti-neoplastic and chemopreventive agent for lung cancer.
Larry Massie - One of the best experts on this subject based on the ideXlab platform.
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grape seed procyanidin extract against lung cancer the role of microrna 106b bioavailability and bioactivity
Oncotarget, 2018Co-Authors: Bingye Xue, Larry Massie, Clifford Qualls, Jenny T MaoAbstract:// Bingye Xue 1 , Qing-Yi Lu 2 , Larry Massie 3 , Clifford Qualls 4 and Jenny T. Mao 1 1 Pulmonary, Critical Care, and Sleep Section, New Mexico Veterans Administration Health Care System, University of New Mexico, Biomedical Research Institute of New Mexico, Albuquerque, NM, USA 2 UCLA Center for Human Nutrition, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA 3 Pathology and Clinical Laboratory Services, New Mexico Veterans Administration Health Care System, University of New Mexico, Albuquerque, NM, USA 4 Biomedical Research Institute of New Mexico, New Mexico Veterans Administration Health Care System, University of New Mexico, Albuquerque, NM, USA Correspondence to: Jenny T. Mao, email: jenny.mao@va.gov Keywords: Oncomir; P21; CDKN1A; pharmacokinetics; pharmacodynamics Received: July 23, 2017 Accepted: February 10, 2018 Epub: February 16, 2018 Published: March 20, 2018 ABSTRACT MiR-106b is an Oncomir and a potential target for anti-cancer therapy. We hypothesize that grape seed procyanidin extract (GSE) exerts antineoplastic effects on lung cancer through modulations of miR-106b and its downstream target. We found that GSE significantly down-regulated miR-106b in a variety of lung neoplastic cells and increased cyclin-dependent kinase inhibitor 1A ( CDKN1A ) mRNA and protein (p21) levels. Transfection of miR-106b mimics reversed the up-regulations of CDKN1A mRNA and p21, abrogated the GSE induced anti-proliferative and anti-invasive properties in lung cancer cells. Oral gavage of leucoselect phytosome (LP), a standardized GSE to athymic nude mice down-regulated MIR106B mRNA and miR-106b expressions, and increased CDKN1A mRNA expression in tumor xenografts, correlating to significant reduction of tumor growth. To assess bioavailability, GSE and metabolites in plasma levels, between 60–90 minutes after gavage of LP were measured by LC/MS at treatment week 4 and 8. A novel bioactivity assay was also developed using lung homogenates from treated mice co-cultured with human lung cancer cells. LP-treated mouse lung homogenates significantly reduced proliferations of various lung cancer cells. Our findings reveal novel antineoplastic mechanisms by GSE, further define the pharmacokinetics and pharmacodynamics of LP, and support the continued investigation of LP against lung cancer.
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microrna 19a b mediates grape seed procyanidin extract induced anti neoplastic effects against lung cancer
Journal of Nutritional Biochemistry, 2016Co-Authors: Jenny T Mao, Bingye Xue, Jane Smoake, Heesung Park, Susanne M Henning, Windie Burns, Alvise Bernabei, David Elashoff, Kenneth J Serio, Larry MassieAbstract:Abstract Oncomirs are microRNAs (miRNA) associated with carcinogenesis and malignant transformation. They have emerged as potential molecular targets for anti-cancer therapy. We hypothesize that grape seed procyanidin extract (GSE) exerts antineoplastic effects through modulations of Oncomirs and their downstream targets. We found that GSE significantly down-regulated Oncomirs miR-19a and -19b in a variety of lung neoplastic cells. GSE also increased mRNA and protein levels of insulin-like growth factor II receptor (IGF-2R) and phosphatase and tensin homolog (PTEN), both predicted targets of miR-19a and -19b. Furthermore, GSE significantly increased PTEN activity and decreased AKT phosphorylation in A549 cells. Transfection of miR-19a and -19b mimics reversed the up-regulations of IGF2R and PTEN gene expression and abrogated the GSE induced anti-proliferative response. Additionally, oral administration of leucoselect phytosome, comprised of standardized grape seed oligomeric procyanidins complexed with soy phospholipids, to athymic nude mice via gavage, significantly down-regulated miR-19a, -19b and the miR-17-92 cluster host gene (MIR17HG) expressions, increased IGF-2R, PTEN, decreased phosphorylated-AKT in A549 xenograft tumors, and markedly inhibited tumor growth. To confirm the absorption of orally administered GSE, plasma procyanidin B1 levels, between 60 and 90 min after gavage of leucoselect phytosome (400 mg/kg), were measured by LC/MS at week 2 and 8 of treatment; the estimated concentration that was associated with 50% growth inhibition (IC 50 ) (1.3 μg/mL) in vitro was much higher than the IC 50 (0.032–0.13 μg/ml) observed in vivo . Our findings reveal novel antineoplastic mechanisms by GSE and support the clinical translation of leucoselect phytosome as an anti-neoplastic and chemopreventive agent for lung cancer.
Hongwei Liang - One of the best experts on this subject based on the ideXlab platform.
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Nuclear miR-122 directly regulates the biogenesis of cell survival Oncomir miR-21 at the posttranscriptional level.
Nucleic acids research, 2017Co-Authors: Dong Wang, Xinlei Sun, Yao Wei, Hongwei Liang, Min Yuan, Fangfang Jin, Xi Chen, Yuan Liu, Chen-yu ZhangAbstract:Hepatic miR-122 can serve as a pro-apoptotic factor to suppress tumorigenesis. The underlying mechanism, however, remains incompletely understood. Here we present the first evidence that miR-122 promotes hepatocellular carcinoma cell apoptosis through directly silencing the biogenesis of cell survival Oncomir miR-21 at posttranscriptional level. We find that miR-122 is strongly expressed in primary liver cell nucleus but its nuclear localization is markedly decreased in transformed cells particularly in chemoresistant tumor cells. MiRNA profiling and RT-qPCR confirm an inverse correlation between miR-122 and miR-21 in hepatocellular carcinoma tissues/cells, and increasing or decreasing nuclear level of miR-122 respectively reduces or increases miR-21 expression. Mechanistically, nuclear miR-122 suppresses miR-21 maturation via binding to a 19-nt UG-containing recognition element in the basal region of pri-miR-21 and preventing the Drosha-DGCR8 microprocessor's conversion of pri-miR-21 into pre-miR-21. Furthermore, both in vitro and in vivo studies demonstrate that nuclear miR-122 participates in the regulation of HCC cell apoptosis through modulating the miR-21-targeted programmed cell death 4 (PDCD4) signal pathway.
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mir 23a b promote tumor growth and suppress apoptosis by targeting pdcd4 in gastric cancer
Cell Death and Disease, 2017Co-Authors: Xiuting Hu, Hongwei Liang, Chen-yu Zhang, Yanbo Wang, Weijie Zhang, Zhen Zhou, Xi ChenAbstract:MicroRNAs (miRNAs) are short non-coding RNAs of 21–23 nucleotides that play important roles in virtually all biological pathways in mammals and in other multicellular organisms. miR-23a and miR-23b (miR-23a/b) are critical Oncomirs (miRNAs that are associated with human cancers) of gastric cancer, but their detailed roles in the initiation and progression of gastric cancer remain to be elucidated. In this study, we found that miR-23a/b were consistently upregulated in gastric cancer tissues. We then investigated the molecular mechanisms through which miR-23a/b contribute to gastric cancer and identified programmed cell death 4 (PDCD4) as a direct target gene of miR-23a/b. In contrast to the upregulated expression levels of miR-23a/b, PDCD4 protein levels were dramatically downregulated and inversely correlated with miR-23a/b in gastric cancer tissues. Moreover, we observed that cell apoptosis was increased by miR-23a/b inhibitors and decreased by miR-23a/b mimics in gastric cancer cells and that the restoration of PDCD4 expression attenuated the anti-apoptotic effects of miR-23a/b in gastric cancer cells, indicating that PDCD4 is a direct mediator of miR-23a/b functions. Finally, we showed that miR-23a/b significantly suppressed PDCD4 expression and enhanced tumor growth in a gastric cancer xenograft mouse model. Taken together, this study highlights an important role for miR-23a/b as Oncomirs in gastric cancer through the inhibition of PDCD4 translation. These findings may shed new light on the molecular mechanism of gastric carcinogenesis and provide a new avenue for gastric cancer treatment.
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mir 181b functions as an Oncomir in colorectal cancer by targeting pdcd4
Protein & Cell, 2016Co-Authors: Yanqing Liu, Hongwei Liang, Yu Guo, Rongjie Cheng, Fei Yang, Yeting Hong, Chihao Zhao, Minghui Liu, Xinyan Zhou, Kai YinAbstract:Programmed cell death 4 (PDCD4) is a RNA-binding protein that acts as a tumor suppressor in many cancer types, including colorectal cancer (CRC). During CRC carcinogenesis, PDCD4 protein levels remarkably decrease, but the underlying molecular mechanism for decreased PDCD4 expression is not fully understood. In this study, we performed bioinformatics analysis to identify miRNAs that potentially target PDCD4. We demonstrated miR-181b as a direct regulator of PDCD4. We further showed that activation of IL6/STAT3 signaling pathway increased miR-181b expression and consequently resulted in downregulation of PDCD4 in CRC cells. In addition, we investigated the biological effects of PDCD4 inhibition by miR-181b both in vitro and in vivo and found that miR-181b could promote cell proliferation and migration and suppress apoptosis in CRC cells and accelerate tumor growth in xenograft mice, potentially through targeting PDCD4. Taken together, this study highlights an Oncomir role for miR-181b in regulating PDCD4 in CRC and suggests that miR-181b may be a novel molecular therapeutic target for CRC.
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mir 93 functions as an Oncomir for the downregulation of pdcd4 in gastric carcinoma
Scientific Reports, 2016Co-Authors: Hongwei Liang, Weijie Zhang, Feng Wang, Danping Chu, Zhicong Liao, Xin Yan, Hao Zhu, Wen Guo, Yujing Zhang, Wenxian GuanAbstract:Programmed cell death 4 (PDCD4), as a tumor suppressor gene, is frequently reduced in a variety of tumors, including gastric cancer. Previous findings have indicated that PDCD4 participates in tumorigenesis through the regulation of apoptosis, but the molecular basis of this process has not been fully elucidated, and no studies have shown the upstream regulation of this gene in gastric cancer. In this study, we used bioinformatics analysis to search for miRNAs that could potentially target PDCD4 and identified miR-93 as a candidate. Moreover, we observed the inverse correlation between miR-93 and PDCD4 protein levels, but not mRNA levels, in human gastric cancer tissues. We further experimentally validated PDCD4 as the direct target of miR-93 by evaluating PDCD4 expression in gastric cancer cells after the overexpression or knockdown of miR-93. Additionally, the biological consequences of targeting PDCD4 through miR-93 were examined using cell apoptosis assays in vitro. We demonstrated that the repression of PDCD4 through miR-93 suppressed the apoptosis of gastric cancer cells. Finally, we revealed that miR-93 promoted the development of gastric tumor growth in xenograft mice by negatively regulating PDCD4. Taken together, the findings of the present study indicated the oncogenic role of miR-93 in gastric cancer tumorigenesis through targeting PDCD4, particularly in apoptosis.
Rafael Malagoli Rocha - One of the best experts on this subject based on the ideXlab platform.
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abstract 1106 mir 223 5p works as an Oncomir in vulvar carcinoma by tp63 regulation
Cancer Research, 2016Co-Authors: Rafael Malagoli Rocha, Beatriz De Melo Maia, Iara S Rodrigues, Nayra Soares Do Amaral, Hui Ling, George A Calin, Fernando Augusto SoaresAbstract:Recently, miR-223-5p was associated with metastasis in HPV negative vulvar samples and in several other tumor types. In the present study, we hypothesized that this microRNA would have a potential impact on in vitro vulvar cancer behavior. We artificially mimicked microRNA expression in vulvar cancer cell line, SW962, derived from lymph node metastasis of vulvar carcinoma, and performed in vitro assays as follows in the result section. Impaired cell proliferation (p Citation Format: Rafael Rocha, Beatriz De Melo Maia, Iara S. Rodrigues, Nayra S. Amaral, Hui Ling, George A. Calin, Fernando A. Soares. Mir-223-5p works as an Oncomir in vulvar carcinoma by TP63 regulation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1106.
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mir 223 5p works as an Oncomir in vulvar carcinoma by tp63 suppression
Oncotarget, 2016Co-Authors: Beatriz De Melo Maia, Iara S Rodrigues, Nayra Soares Do Amaral, Hui Ling, George A Calin, Fernando Augusto Soares, Erica Mie Akagi, Paloma Monroig, Rafael Malagoli RochaAbstract:// Beatriz de Melo Maia 1, 2 , Iara Santana Rodrigues 1 , Erica Mie Akagi 1 , Nayra Soares do Amaral 1 , Hui Ling 2 , Paloma Monroig 2 , Fernando Augusto Soares 1 , George Adrian Calin 2, 3 , Rafael Malagoli Rocha 4 1 Molecular Morphology Laboratory, Anatomic Pathology Department, AC Camargo Cancer Center, Sao Paulo, Brazil 2 Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA 3 The Center for RNA Interference and Non-Coding RNAs, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA 4 Gynecology Laboratory, Gynecologic Department Federal University of Sao Paulo, Sao Paulo, Brazil Correspondence to: Rafael Malagoli Rocha, email: rafael.malagoli@gmail.com Keywords: vulvar cancer, microRNAs, cellular assays, hsa-miR-223-5p, TP63 Received: January 11, 2016 Accepted: May 08, 2016 Published: June 23, 2016 ABSTRACT MiR-223-5p has been previously mentioned to be associated with tumor metastasis in HPV negative vulvar carcinomas, such as in several other tumor types. In the present study, we hypothesized that this microRNA would be important in vulvar cancer carcinogenesis and progression. To investigate this, we artificially mimicked miR-223-5p expression in a cell line derived from lymph node metastasis of vulvar carcinoma (SW962) and performed in vitro assays. As results, lower cell proliferation ( p < 0.01) and migration ( p < 0.001) were observed when miR-223-5p was overexpressed. In contrast, increased invasive potential of these cells was verified ( p < 0.004). In silico search indicated that miR-223-5p targets TP63 , member of the TP53 family of proteins, largely described with importance in vulvar cancer. We experimentally demonstrated that this microRNA is capable to decrease levels of p63 at both mRNA and protein levels ( p < 0.001, and p < 0.0001; respectively). Also, a significant inverse correlation was observed between miR-223-5p and p63 expressions in tumors from patients ( p = 0.0365). Furthermore, low p63 protein expression was correlated with deeper tumor invasion ( p = 0.0491) and lower patient overall survival ( p = 0.0494). Our study points out miR-223-5p overexpression as a putative pathological mechanism of tumor invasion and a promising therapeutic target and highlights the importance of both miR-223-5p and p63 as prognostic factors in vulvar cancer. Also, it is plausible that the evaluation of p63 expression in vulvar cancer at the biopsy level may bring important contribution on prognostic establishment and in elaborating better surgical approaches for vulvar cancer patients.
