MicroRNA-217, down-regulated in clear cell renal cell carcinoma and associated with lower survival, suppresses cell proliferation and migration

H, Li; Zhao, Jiajun; Zhang, JW; Qy, Huang; Jz, Huang; Ls, Chi; Hj, Tang; Gq, Liu; Dj, Zhu; Wm, Ma

doi:10.4149/neo_2013_066

Cited by 52 publications

(45 citation statements)

References 14 publications

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“…Our results are consistent with the notion that these miRNAs regulate numerous genes that promote tumor progression and which may be expressed differentially in different metastatic tumors. Notably, miR-216b and miR-217 have previously been implicated as inhibitors of tumor growth and invasion in nasopharyngeal, renal clear cell, and pancreatic ductal carcinoma (Deng et al 2011;Ali et al 2012;Li et al 2013b). Further, each member of the Mir216/ 217 cluster was demonstrated to possess a significant cis-acting eQTL, indicating that differences in Mir216/217 expression across the AKXD RI panel are inherited and not acquired somatically during neoplastic transformation or tumor progression.…”

Section: Discussionmentioning

confidence: 93%

An integrated systems genetics screen reveals the transcriptional structure of inherited predisposition to metastatic disease

Faraji

et al. 2013

Genome Res.

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Metastasis is the result of stochastic genomic and epigenetic events leading to gene expression profiles that drive tumor dissemination. Here we exploit the principle that metastatic propensity is modified by the genetic background to generate prognostic gene expression signatures that illuminate regulators of metastasis. We also identify multiple microRNAs whose germline variation is causally linked to tumor progression and metastasis. We employ network analysis of global gene expression profiles in tumors derived from a panel of recombinant inbred mice to identify a network of co-expressed genes centered on Cnot2 that predicts metastasis-free survival. Modulating Cnot2 expression changes tumor cell metastatic potential in vivo, supporting a functional role for Cnot2 in metastasis. Small RNA sequencing of the same tumor set revealed a negative correlation between expression of the Mir216/217 cluster and tumor progression. Expression quantitative trait locus analysis (eQTL) identified cis-eQTLs at the Mir216/217 locus, indicating that differences in expression may be inherited. Ectopic expression of Mir216/217 in tumor cells suppressed metastasis in vivo. Finally, small RNA sequencing and mRNA expression profiling data were integrated to reveal that miR-3470a/b target a high proportion of network transcripts. In vivo analysis of Mir3470a/b demonstrated that both promote metastasis. Moreover, Mir3470b is a likely regulator of the Cnot2 network as its overexpression down-regulated expression of network hub genes and enhanced metastasis in vivo, phenocopying Cnot2 knockdown. The resulting data from this strategy identify Cnot2 as a novel regulator of metastasis and demonstrate the power of our systems-level approach in identifying modifiers of metastasis.[Supplemental material is available for this article.]Metastasis is a systemic disease responsible for the majority of cancer-related mortality and is influenced by both tumor cell-autonomous and host-derived factors. Its complexity is deepened by involvement of not only stochastic genomic and epigenetic events but also by inherited predisposition (Lifsted et al. 1998;Crawford et al. 2006). As a result, despite identification and characterization of individual genes, cellular and developmental processes associated with metastasis, understanding of the metastatic cascade and the interconnectivity of individual factors remains limited. The elucidation of higher-order networks underlying metastasis will therefore likely improve prognostication and intervention strategies by identifying molecular nodes central to tumor cell dissemination and colonization.Recent advances in global gene expression profiling and computational science have provided the basis for understanding cancer biology at a systems level (Quigley et al. 2009). Knowledge of both tumor subtypes (Perou et al. 2000) and patient prognosis has been enhanced by systems-based approaches. This knowledge may significantly change clinical practice by enabling the development of precision treatments based on mol...

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Section: Discussionmentioning

confidence: 93%

An integrated systems genetics screen reveals the transcriptional structure of inherited predisposition to metastatic disease

Faraji

et al. 2013

Genome Res.

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“…Similarly, miR-375 is associated with drug resistance in ovarian (71) and cervical cancer (72). Although no study has reported the role of miR-32 and -217 in drug resistance, it is associated with drug resistance-related processes such as cell proliferation, invasion and migration (73)(74)(75). Collectively, among the 7 microRNAs most strongly targeting HNF1B, the majority were involved in drug resistance in ovarian and other types of cancers, suggesting that the gene also mediates drug resistance.…”

Section: Microrna-mrna Interaction Analysis Indicating the Associatiomentioning

confidence: 99%

Downregulation of HNF1 homeobox B is associated with drug resistance in ovarian cancer

Zhang²,

Gao

et al. 2014

Oncology Reports

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Abstract. The expression of HNF1 homeobox B (HNF1B) is associated with cancer risk in several tumors, including ovarian cancer, and its decreased expression play roles in cancer development. However, the study of HNF1B and cancer is limited, and its association with drug resistance in cancer has never been reported. On the basis of array data retrieved from Oncomine and Gene Expression Omnibus (GEO) online database, we found that the mRNA expression of HNF1B in 586 ovarian serous cystadenocarcinomas and in platinum-resistant A2780 epithelial ovarian cancer cells was significantly decreased, indicating a potential role of HNF1B in drug resistance in ovarian cancer. Based on this finding, comprehensive bioinformatics analyses, including protein/ gene interaction, protein-small molecule/chemical interaction, biological process annotation, gene co-occurrence and pathway enrichment analysis and microRNA-mRNA interaction, were performed to illustrate the association of HNF1B with drug resistance in ovarian cancer. We found that among the proteins/ genes, small molecules/chemicals and microRNAs which directly interacted with HNF1B, the majority was associated with drug resistance in cancer, particularly in ovarian cancer. Biological process annotation revealed that HNF1B closely related to 24 biological processes which were all notably associated with ovarian cancer and drug resistance. These results indicated that the downregulation of HNF1B may contribute to drug resistance in ovarian cancer, via its direct interactions with these drug resistance-related proteins/genes, small molecules/chemicals and microRNAs, and via its regulations on the drug resistance-related biological processes. Pathway enrichment analysis of 36 genes which co-occurred with HNF1B, ovarian cancer and drug resistance indicated that the HNF1B may perform its drug resistance-related functions through 4 pathways including ErbB signaling, focal adhesion, apoptosis and p53 signaling. Collectively, in this study, we illustrated for the first time that HNF1B may contribute to drug resistance in ovarian cancer, potentially through the 4 pathways. The present study may pave the way for further investigation of the drug resistance-related functions of HNF1B in ovarian cancer.

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“…In hepatocellular carcinoma, endogenous miR-217 expression inhibited cell invasion by directly targeting E2F transcription factor 3 (26). In clear cell renal cell carcinoma, ectopic expression of miR-217 suppressed cell proliferation, migration and invasion (27). These studies indicate that miR-217 mainly functions as a tumor suppressor in several types of cancer.…”

Section: Discussionmentioning

confidence: 75%

“…The low expression level of miR-217 was notably correlated with tumor differentiation and shorter overall survival for patients with colorectal cancer (24). Additionally, miR-217 was found to be downregulated in lung (25), hepatocellular (26) and clear cell renal cell carcinoma (27) and pancreatic ductal adenocarcinoma (28). However, in breast cancer, miR-217 was upregulated in tumor tissues in comparison with normal breast tissues.…”

Section: Discussionmentioning

confidence: 84%

MicroRNA 217 inhibits cell proliferation and enhances chemosensitivity to doxorubicin in acute myeloid leukemia by targeting KRAS

Xiao

Deng

et al. 2017

Oncology Letters

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Abstract. Acute myeloid leukemia (AML) is a heterogeneous malignant disorder derived from the myeloid hematopoietic cells that accounts for ~80% of all adult acute leukemia. Numerous studies have shown that drug resistance not only exists against conventional chemotherapeutic drugs, but also limits the efficacy of new biological agents. Therefore, it is important to identify the mechanisms behind chemoresistance and seek therapeutic strategies to enhance efficacy in AML chemotherapy. MicroRNA (miR)-217 has been recognized as a tumor suppressor that is downregulated in various types of cancer, however the mechanisms behind the expression and function of miR-217 in AML have not yet been recognized. The expression of miR-217 was determined by quantitative polymerase chain reaction (qPCR). Following transfection with miR-217 mimics, an MTT assay, chemosensitivity assay, cell apoptosis assay and western blot analysis were performed in AML cell lines. Functional assays were also performed to explore the effects of endogenous Kirsten rat sarcoma viral oncogene homolog (KRAS) in AML. The results revealed that miR-217 was downregulated in patients with AML. Overexpression of miR-217 inhibited cellular proliferation and enhanced cell chemosensitivity to doxorubicin by the cell apoptosis pathway in AML cells. A dual-luciferase reporter assay demonstrated that KRAS was a direct target gene of miR-217 in vitro. qPCR and western blot analysis revealed that miR-217 negatively regulated KRAS protein expression, but had no impact on KRAS mRNA expression. Knockdown of KRAS expression markedly suppressed AML cellular proliferation, and enhanced cell chemosensitivity to doxorubicin via the cell apoptosis pathway. These findings indicate that miR-217 functions as a tumor suppressor in AML by directly targeting KRAS. Therefore, miR-217-based therapeutic strategies may provide a novel strategy for the enhancement of efficacy in the treatment of AML.

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MicroRNA-217, down-regulated in clear cell renal cell carcinoma and associated with lower survival, suppresses cell proliferation and migration

Cited by 52 publications

References 14 publications

An integrated systems genetics screen reveals the transcriptional structure of inherited predisposition to metastatic disease

An integrated systems genetics screen reveals the transcriptional structure of inherited predisposition to metastatic disease

Downregulation of HNF1 homeobox B is associated with drug resistance in ovarian cancer

MicroRNA 217 inhibits cell proliferation and enhances chemosensitivity to doxorubicin in acute myeloid leukemia by targeting KRAS

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