MYC pathway is activated in clear cell renal cell carcinoma and essential for proliferation of clear cell renal cell carcinoma cells

Tang, Sai-Wen; Chang, W. H.; Su, Yih-Ching; Chen, Yu‐Chi; Lai, Yen-Han; Wu, Pei-Tzu; Hsu, Chih-Chao; Lin, Wei-Chou; Lai, Ming-Kuen; Lin, Jung‐Yaw

doi:10.1016/j.canlet.2008.07.038

Cited by 114 publications

(105 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, the application of different bioinformatics tools resulted in a list of genes (e.g., VEGFA, MYC, CA9, SLC2A1, BNIP3, CXCR4, EGLN3 alias PDH3, SERPINA1, KDR, ATM, CP) highly activated in ccRCC and related to hypoxia signaling, known to be targets of the transcription factor HIF-1 or involved in cancer and pathways (as apoptosis and angiogenesis) which have been already targeted for therapeutic intervention in RCC (Pantuck et al, 2003). As expected, among the up-regulated genes, there is the well-known cancer gene MYC (Gordan, 2007(Gordan, , 2008) that several studies indicated as modulated by HIF-1 (Dang, 2008;Gordan, 2007;Podar & Anderson, 2010) and playing a fundamental role in ccRCC proliferation (Tang et al, 2009). …”

Section: Discussionsupporting

confidence: 55%

Molecular Portrait of Clear Cell Renal Cell Carcinoma: An Integrative Analysis of Gene Expression and Genomic Copy Number Profiling

Battaglia¹,

Mangano²,

Bicciato³

et al. 2012

Emerging Research and Treatments in Renal Cell Carcinoma

View full text Add to dashboard Cite

Section: Discussionsupporting

confidence: 55%

Molecular Portrait of Clear Cell Renal Cell Carcinoma: An Integrative Analysis of Gene Expression and Genomic Copy Number Profiling

Battaglia¹,

Mangano²,

Bicciato³

et al. 2012

Emerging Research and Treatments in Renal Cell Carcinoma

View full text Add to dashboard Cite

“…(25,26) Moreover, c-MYC has also been reported to be upregulated in RCC clinical specimens. (27)(28)(29)(30) Thus, our data suggest that the identification of tumor-suppressive miR-135a-mediated cancer pathways may provide insights into potential therapeutic targets for the treatment of RCC.…”

mentioning

confidence: 79%

“…(43)(44)(45) Several reports have shown that the c-MYC pathway is activated in RCC due to the overexpression and amplification of the c-MYC gene. (27,30) For example, CCND1, which is considered a proto-oncogene, promotes the G 1 ⁄ S phase transition in the progression of the cell cycle by regulating cyclin-dependent kinase activity. (46,47) In the current study, our expression profile analysis identified CCND1 as an miR-135a regulated gene involved in cancer-related and cell cycle pathways, supporting previous studies.…”

Section: Discussionmentioning

confidence: 99%

Tumor‐suppressive microRNA‐135a inhibits cancer cell proliferation by targeting the c‐MYC oncogene in renal cell carcinoma

et al. 2012

View full text Add to dashboard Cite

Recently, many studies have suggested that microRNAs (miRNAs) are involved in cancer cell development, invasion, and metastasis of various types of human cancers. In a previous study, miRNA expression signatures from renal cell carcinoma (RCC) revealed that expression of microRNA-135a (miR-135a) was significantly reduced in cancerous tissues. The aim of this study was to investigate the functional significance of miR-135a and to identify miR-135a-mediated molecular pathways in RCC cells. Restoration of mature miR-135a significantly inhibited cancer cell proliferation and induced G 0 ⁄ G 1 arrest in the RCC cell lines caki2 and A498, suggesting that miR-135a functioned as a potential tumor suppressor. We then examined miR-135a-mediated molecular pathways using genome-wide gene expression analysis and in silico analysis. A total of 570 downregulated genes were identified in miR-135a transfected RCC cell lines. To investigate the biological significance of potential miR-135a-mediated pathways, we classified putative miR-135a-regulated genes according to the Kyoto Encyclopedia of Genes and Genomics pathway database. From our in silico analysis, 25 pathways, including the cell cycle, pathways in cancer, DNA replication, and focal adhesion, were significantly regulated by miR-135a in RCC cells. Moreover, based on the results of this analysis, we investigated whether miR-135a targeted the c-MYC gene in RCC. Gain-of-function and luciferase reporter assays showed that c-MYC was directly regulated by miR-135a in RCC cells. Furthermore, c-MYC expression was significantly upregulated in RCC clinical specimens. Our data suggest that elucidation of tumor-suppressive miR-135a-mediated molecular pathways could reveal potential therapeutic targets in RCC. (Cancer Sci 2013; 104: 304-312) R enal cell carcinoma (RCC) is the most common neoplasm of the adult kidney, and approximately 80% of RCC patients are diagnosed with the clear cell RCC (ccRCC) subtype.(1) In the USA, the incidence and mortality rates of RCC have increased in recent years, with approximately 58 000 new cases and 13 000 deaths in 2010.(2) Although surgery is curative for localized disease, a significant percentage of patients developed relapses or metastases with poor prognosis.(3,4) Therefore, researchers have become interested in elucidating the molecular mechanisms of RCC oncogenesis and metastasis, which could lead to development of better prognostic, diagnostic, and therapeutic interventions for the disease.RNA can be divided into two categories, protein-coding RNAs and non-coding RNAs (ncRNAs). It is important to examine the functions of ncRNAs in both normal and diseased tissues and to elucidate their involvement in human diseases, including cancer. MicroRNAs (miRNAs) are endogenous small ncRNA molecules (19-22 bases) that regulate protein-coding gene expression by repressing translation of RNA or cleaving RNA transcripts in a sequence-specific manner.(5) A growing body of evidence suggests that miRNAs are aberrantly expressed in many human cancers and ...

show abstract

“…22 In Burkitt's lymphoma, ZONAB is a target for c-Myc, 21 also involved in RCCs. 32 Although no repressor of ZONAB is known, an attractive candidate is p53, which represses proliferation genes (PCNA, cdc2) while inducing cellcycle arrest genes (p21) and renal function genes. 33 Regulation by proteasomal degradation has been reported for multiple transcription factors such as the ZONAB-related, YB-1, and hypoxia-inducible factor but without direct link with epithelial polarization.…”

Section: Discussionmentioning

confidence: 99%

ZONAB Promotes Proliferation and Represses Differentiation of Proximal Tubule Epithelial Cells

Lima

Parreira

Devuyst

et al. 2010

Journal of the American Society of Nephrology

100

View full text Add to dashboard Cite

Epithelial polarization modulates gene expression. The transcription factor zonula occludens 1 (ZO-1)-associated nucleic acid binding protein (ZONAB) can shuttle between tight junctions and nuclei, promoting cell proliferation and expression of cyclin D1 and proliferating cell nuclear antigen (PCNA), but whether it also represses epithelial differentiation is unknown. Here, during mouse kidney ontogeny and polarization of proximal tubular cells (OK cells), ZONAB and PCNA levels decreased in parallel and inversely correlated with increasing apical differentiation, reflected by expression of megalin/cubilin, maturation of the brush border, and extension of the primary cilium. Conversely, ZONAB reexpression and loss of apical differentiation markers provided a signature for renal clear cell carcinoma. In confluent OK cells, ZONAB overexpression increased proliferation and PCNA while repressing megalin/cubilin expression and impairing differentiation of the brush border and primary cilium. Reporter and chromatin immunoprecipitation assays demonstrated that megalin and cubilin are ZONAB target genes. Sparsely plated OK cells formed small islands composed of distinct populations: Cells on the periphery, which lacked external tight junctions, strongly expressed nuclear ZONAB, proliferated, and failed to differentiate; central cells, surrounded by continuous junctions, lost nuclear ZONAB, stopped proliferating, and engaged in apical differentiation. Taken together, these data suggest that ZONAB is an important component of the mechanisms that sense epithelial density and participates in the complex transcriptional networks that regulate the switch between proliferation and differentiation.

show abstract

MYC pathway is activated in clear cell renal cell carcinoma and essential for proliferation of clear cell renal cell carcinoma cells

Cited by 114 publications

References 35 publications

Molecular Portrait of Clear Cell Renal Cell Carcinoma: An Integrative Analysis of Gene Expression and Genomic Copy Number Profiling

Molecular Portrait of Clear Cell Renal Cell Carcinoma: An Integrative Analysis of Gene Expression and Genomic Copy Number Profiling

Tumor‐suppressive microRNA‐135a inhibits cancer cell proliferation by targeting the c‐MYC oncogene in renal cell carcinoma

ZONAB Promotes Proliferation and Represses Differentiation of Proximal Tubule Epithelial Cells

Contact Info

Product

Resources

About