MiR-141 Is a key regulator of renal cell carcinoma proliferation and metastasis by controlling EphA2 expression

Xuanyu Chen, Xuegang Wang, Anming Ruan, Weiwei Han, Yan Zhao, Xing Lu, Pei Xiao, Hangchuan Shi, Rong Wang, Li Chen, Shaoyong Chen, Quansheng Du, Hongmei Yang, Xiaoping Zhang

Research output: Contribution to journalArticle

90 Citations (Scopus)

Abstract

Purpose: Although microRNAs (miRNA) have been revealed as crucial modulators of tumorigenesis, our understanding of their roles in renal cell carcinoma (RCC) is limited. Here we sought to identify human miRNAs that act as key regulators of renal carcinogenesis. Experimental Design: We performed microarray-based miRNA profiling of clear cell RCC (ccRCC) and adjacent normal tissues and then explored the roles of miR-141 both in vitro and in vivo, which was the most significantly downregulated in ccRCC tissues. Results: A total of 74 miRNAs were dysregulated in ccRCC compared with normal tissues. miR-141 was remarkably downregulated in 92.6% (63/68) ccRCC tissues and would serve as a promising biomarker for discriminating ccRCC from normal tissues with an area under the receiver operating characteristics curve of 0.93. Overexpression of miR-141 robustly impaired ccRCC cell migratory and invasive properties and suppressed cell proliferation by arresting cells at G0-G1 phase in vitro and in human RCC orthotopic xenografts. Significantly, the antitumor activities of miR-141 were mediated by its reversal regulation of erythropoietin-producing hepatocellular (Eph) A2 (EphA2), which then relayed a signaling transduction cascade to attenuate the functions of focal adhesion kinase (FAK), AKT, and MMP2/9. In addition, a specific and inverse correlation between miR-141 and EphA2 expression was obtained in human ccRCC samples. Finally, miR-141 could be secreted from the ccRCC donor cells, and be taken up and function moderately in the ccRCC recipient cells. Conclusion: miR-141 serves as a potential biomarker for discriminating ccRCC from normal tissues and a crucial suppressor of ccRCC cell proliferation and metastasis by modulating the EphA2/p-FAK/p-AKT/MMPs signaling cascade.

Original languageEnglish (US)
Pages (from-to)2617-2630
Number of pages14
JournalClinical Cancer Research
Volume20
Issue number10
DOIs
StatePublished - May 15 2014

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Renal Cell Carcinoma
varespladib methyl
Cell Proliferation
Neoplasm Metastasis
MicroRNAs
Focal Adhesion Protein-Tyrosine Kinases
Carcinogenesis
Down-Regulation
Biomarkers
Clear-cell metastatic renal cell carcinoma
Cell Cycle Resting Phase
G1 Phase
Erythropoietin
Matrix Metalloproteinases
Heterografts
ROC Curve
Research Design
Kidney

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

MiR-141 Is a key regulator of renal cell carcinoma proliferation and metastasis by controlling EphA2 expression. / Chen, Xuanyu; Wang, Xuegang; Ruan, Anming; Han, Weiwei; Zhao, Yan; Lu, Xing; Xiao, Pei; Shi, Hangchuan; Wang, Rong; Chen, Li; Chen, Shaoyong; Du, Quansheng; Yang, Hongmei; Zhang, Xiaoping.

In: Clinical Cancer Research, Vol. 20, No. 10, 15.05.2014, p. 2617-2630.

Research output: Contribution to journalArticle

Chen, X, Wang, X, Ruan, A, Han, W, Zhao, Y, Lu, X, Xiao, P, Shi, H, Wang, R, Chen, L, Chen, S, Du, Q, Yang, H & Zhang, X 2014, 'MiR-141 Is a key regulator of renal cell carcinoma proliferation and metastasis by controlling EphA2 expression', Clinical Cancer Research, vol. 20, no. 10, pp. 2617-2630. https://doi.org/10.1158/1078-0432.CCR-13-3224
Chen, Xuanyu ; Wang, Xuegang ; Ruan, Anming ; Han, Weiwei ; Zhao, Yan ; Lu, Xing ; Xiao, Pei ; Shi, Hangchuan ; Wang, Rong ; Chen, Li ; Chen, Shaoyong ; Du, Quansheng ; Yang, Hongmei ; Zhang, Xiaoping. / MiR-141 Is a key regulator of renal cell carcinoma proliferation and metastasis by controlling EphA2 expression. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 10. pp. 2617-2630.
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abstract = "Purpose: Although microRNAs (miRNA) have been revealed as crucial modulators of tumorigenesis, our understanding of their roles in renal cell carcinoma (RCC) is limited. Here we sought to identify human miRNAs that act as key regulators of renal carcinogenesis. Experimental Design: We performed microarray-based miRNA profiling of clear cell RCC (ccRCC) and adjacent normal tissues and then explored the roles of miR-141 both in vitro and in vivo, which was the most significantly downregulated in ccRCC tissues. Results: A total of 74 miRNAs were dysregulated in ccRCC compared with normal tissues. miR-141 was remarkably downregulated in 92.6{\%} (63/68) ccRCC tissues and would serve as a promising biomarker for discriminating ccRCC from normal tissues with an area under the receiver operating characteristics curve of 0.93. Overexpression of miR-141 robustly impaired ccRCC cell migratory and invasive properties and suppressed cell proliferation by arresting cells at G0-G1 phase in vitro and in human RCC orthotopic xenografts. Significantly, the antitumor activities of miR-141 were mediated by its reversal regulation of erythropoietin-producing hepatocellular (Eph) A2 (EphA2), which then relayed a signaling transduction cascade to attenuate the functions of focal adhesion kinase (FAK), AKT, and MMP2/9. In addition, a specific and inverse correlation between miR-141 and EphA2 expression was obtained in human ccRCC samples. Finally, miR-141 could be secreted from the ccRCC donor cells, and be taken up and function moderately in the ccRCC recipient cells. Conclusion: miR-141 serves as a potential biomarker for discriminating ccRCC from normal tissues and a crucial suppressor of ccRCC cell proliferation and metastasis by modulating the EphA2/p-FAK/p-AKT/MMPs signaling cascade.",
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T1 - MiR-141 Is a key regulator of renal cell carcinoma proliferation and metastasis by controlling EphA2 expression

AU - Chen, Xuanyu

AU - Wang, Xuegang

AU - Ruan, Anming

AU - Han, Weiwei

AU - Zhao, Yan

AU - Lu, Xing

AU - Xiao, Pei

AU - Shi, Hangchuan

AU - Wang, Rong

AU - Chen, Li

AU - Chen, Shaoyong

AU - Du, Quansheng

AU - Yang, Hongmei

AU - Zhang, Xiaoping

PY - 2014/5/15

Y1 - 2014/5/15

N2 - Purpose: Although microRNAs (miRNA) have been revealed as crucial modulators of tumorigenesis, our understanding of their roles in renal cell carcinoma (RCC) is limited. Here we sought to identify human miRNAs that act as key regulators of renal carcinogenesis. Experimental Design: We performed microarray-based miRNA profiling of clear cell RCC (ccRCC) and adjacent normal tissues and then explored the roles of miR-141 both in vitro and in vivo, which was the most significantly downregulated in ccRCC tissues. Results: A total of 74 miRNAs were dysregulated in ccRCC compared with normal tissues. miR-141 was remarkably downregulated in 92.6% (63/68) ccRCC tissues and would serve as a promising biomarker for discriminating ccRCC from normal tissues with an area under the receiver operating characteristics curve of 0.93. Overexpression of miR-141 robustly impaired ccRCC cell migratory and invasive properties and suppressed cell proliferation by arresting cells at G0-G1 phase in vitro and in human RCC orthotopic xenografts. Significantly, the antitumor activities of miR-141 were mediated by its reversal regulation of erythropoietin-producing hepatocellular (Eph) A2 (EphA2), which then relayed a signaling transduction cascade to attenuate the functions of focal adhesion kinase (FAK), AKT, and MMP2/9. In addition, a specific and inverse correlation between miR-141 and EphA2 expression was obtained in human ccRCC samples. Finally, miR-141 could be secreted from the ccRCC donor cells, and be taken up and function moderately in the ccRCC recipient cells. Conclusion: miR-141 serves as a potential biomarker for discriminating ccRCC from normal tissues and a crucial suppressor of ccRCC cell proliferation and metastasis by modulating the EphA2/p-FAK/p-AKT/MMPs signaling cascade.

AB - Purpose: Although microRNAs (miRNA) have been revealed as crucial modulators of tumorigenesis, our understanding of their roles in renal cell carcinoma (RCC) is limited. Here we sought to identify human miRNAs that act as key regulators of renal carcinogenesis. Experimental Design: We performed microarray-based miRNA profiling of clear cell RCC (ccRCC) and adjacent normal tissues and then explored the roles of miR-141 both in vitro and in vivo, which was the most significantly downregulated in ccRCC tissues. Results: A total of 74 miRNAs were dysregulated in ccRCC compared with normal tissues. miR-141 was remarkably downregulated in 92.6% (63/68) ccRCC tissues and would serve as a promising biomarker for discriminating ccRCC from normal tissues with an area under the receiver operating characteristics curve of 0.93. Overexpression of miR-141 robustly impaired ccRCC cell migratory and invasive properties and suppressed cell proliferation by arresting cells at G0-G1 phase in vitro and in human RCC orthotopic xenografts. Significantly, the antitumor activities of miR-141 were mediated by its reversal regulation of erythropoietin-producing hepatocellular (Eph) A2 (EphA2), which then relayed a signaling transduction cascade to attenuate the functions of focal adhesion kinase (FAK), AKT, and MMP2/9. In addition, a specific and inverse correlation between miR-141 and EphA2 expression was obtained in human ccRCC samples. Finally, miR-141 could be secreted from the ccRCC donor cells, and be taken up and function moderately in the ccRCC recipient cells. Conclusion: miR-141 serves as a potential biomarker for discriminating ccRCC from normal tissues and a crucial suppressor of ccRCC cell proliferation and metastasis by modulating the EphA2/p-FAK/p-AKT/MMPs signaling cascade.

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