Pseudohypoxia induced by miR-126 deactivation promotes migration and therapeutic resistance in renal cell carcinoma

Weijun Liu; Hanxiang Chen; Nathan Wong; Wesley Haynes; Callie M. Baker; Xiaowei Wang

doi:10.1016/j.canlet.2017.02.025

Pseudohypoxia induced by miR-126 deactivation promotes migration and therapeutic resistance in renal cell carcinoma

Weijun Liu, Hanxiang Chen, Nathan Wong, Wesley Haynes, Callie M. Baker, Xiaowei Wang

Division of Cancer Biology

Research output: Contribution to journal › Article › peer-review

41 Scopus citations

Abstract

Pseudohypoxia plays a central role in the progression and therapeutic resistance of clear cell renal cell carcinoma (ccRCC); however, the underlying mechanisms are poorly understood. MicroRNA miR-126 has decreased expression in metastatic or relapsed ccRCC as compared to primary tumors, but the mechanisms by which miR-126 is implicated in RCC remain unknown. Through RNA-seq profiling to evaluate the impact of overexpression or CRISPR knockout of miR-126, we have identified SERPINE1 as a miR-126-5p target regulating cell motility, and SLC7A5 as a miR-126-3p target regulating the mTOR/HIF pathway. Specifically, miR-126 inhibits HIFα protein expression independent of von Hippel-Lindau tumor suppressor (VHL). On the other hand, deactivation of miR-126 induces a pseudohypoxia state due to increased HIFα expression, which further enhances therapeutic resistance and cell motility mediated by SLC7A5 and SERPINE1, respectively. Finally, the clinical relevance of miR-126 modulated gene regulation in ccRCC has been confirmed with profiling data from The Cancer Genome Atlas.

Original language	English
Pages (from-to)	65-75
Number of pages	11
Journal	Cancer Letters
Volume	394
DOIs	https://doi.org/10.1016/j.canlet.2017.02.025
State	Published - May 28 2017

Keywords

Hypoxia
MicroRNA
Pseudohypoxia
Renal cell carcinoma
miR-126

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title = "Pseudohypoxia induced by miR-126 deactivation promotes migration and therapeutic resistance in renal cell carcinoma",

abstract = "Pseudohypoxia plays a central role in the progression and therapeutic resistance of clear cell renal cell carcinoma (ccRCC); however, the underlying mechanisms are poorly understood. MicroRNA miR-126 has decreased expression in metastatic or relapsed ccRCC as compared to primary tumors, but the mechanisms by which miR-126 is implicated in RCC remain unknown. Through RNA-seq profiling to evaluate the impact of overexpression or CRISPR knockout of miR-126, we have identified SERPINE1 as a miR-126-5p target regulating cell motility, and SLC7A5 as a miR-126-3p target regulating the mTOR/HIF pathway. Specifically, miR-126 inhibits HIFα protein expression independent of von Hippel-Lindau tumor suppressor (VHL). On the other hand, deactivation of miR-126 induces a pseudohypoxia state due to increased HIFα expression, which further enhances therapeutic resistance and cell motility mediated by SLC7A5 and SERPINE1, respectively. Finally, the clinical relevance of miR-126 modulated gene regulation in ccRCC has been confirmed with profiling data from The Cancer Genome Atlas.",

keywords = "Hypoxia, MicroRNA, Pseudohypoxia, Renal cell carcinoma, miR-126",

author = "Weijun Liu and Hanxiang Chen and Nathan Wong and Wesley Haynes and Baker, {Callie M.} and Xiaowei Wang",

note = "Funding Information: We are grateful to Drs. Maria Czyzyk-Krzeska at University of Cincinnati and Xin Huang at University of Pittsburgh for providing RCC cell lines. We thank Drs. Kareem Azab and Qing Yang at Washington University in St. Louis for sharing antibodies. This research was supported by the National Institutes of Health (grant R01GM089784). Publisher Copyright: {\textcopyright} 2017 Elsevier B.V.",

year = "2017",

month = may,

day = "28",

doi = "10.1016/j.canlet.2017.02.025",

language = "English",

volume = "394",

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journal = "Cancer Letters",

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TY - JOUR

T1 - Pseudohypoxia induced by miR-126 deactivation promotes migration and therapeutic resistance in renal cell carcinoma

AU - Liu, Weijun

AU - Chen, Hanxiang

AU - Wong, Nathan

AU - Haynes, Wesley

AU - Baker, Callie M.

AU - Wang, Xiaowei

N1 - Funding Information: We are grateful to Drs. Maria Czyzyk-Krzeska at University of Cincinnati and Xin Huang at University of Pittsburgh for providing RCC cell lines. We thank Drs. Kareem Azab and Qing Yang at Washington University in St. Louis for sharing antibodies. This research was supported by the National Institutes of Health (grant R01GM089784). Publisher Copyright: © 2017 Elsevier B.V.

PY - 2017/5/28

Y1 - 2017/5/28

N2 - Pseudohypoxia plays a central role in the progression and therapeutic resistance of clear cell renal cell carcinoma (ccRCC); however, the underlying mechanisms are poorly understood. MicroRNA miR-126 has decreased expression in metastatic or relapsed ccRCC as compared to primary tumors, but the mechanisms by which miR-126 is implicated in RCC remain unknown. Through RNA-seq profiling to evaluate the impact of overexpression or CRISPR knockout of miR-126, we have identified SERPINE1 as a miR-126-5p target regulating cell motility, and SLC7A5 as a miR-126-3p target regulating the mTOR/HIF pathway. Specifically, miR-126 inhibits HIFα protein expression independent of von Hippel-Lindau tumor suppressor (VHL). On the other hand, deactivation of miR-126 induces a pseudohypoxia state due to increased HIFα expression, which further enhances therapeutic resistance and cell motility mediated by SLC7A5 and SERPINE1, respectively. Finally, the clinical relevance of miR-126 modulated gene regulation in ccRCC has been confirmed with profiling data from The Cancer Genome Atlas.

AB - Pseudohypoxia plays a central role in the progression and therapeutic resistance of clear cell renal cell carcinoma (ccRCC); however, the underlying mechanisms are poorly understood. MicroRNA miR-126 has decreased expression in metastatic or relapsed ccRCC as compared to primary tumors, but the mechanisms by which miR-126 is implicated in RCC remain unknown. Through RNA-seq profiling to evaluate the impact of overexpression or CRISPR knockout of miR-126, we have identified SERPINE1 as a miR-126-5p target regulating cell motility, and SLC7A5 as a miR-126-3p target regulating the mTOR/HIF pathway. Specifically, miR-126 inhibits HIFα protein expression independent of von Hippel-Lindau tumor suppressor (VHL). On the other hand, deactivation of miR-126 induces a pseudohypoxia state due to increased HIFα expression, which further enhances therapeutic resistance and cell motility mediated by SLC7A5 and SERPINE1, respectively. Finally, the clinical relevance of miR-126 modulated gene regulation in ccRCC has been confirmed with profiling data from The Cancer Genome Atlas.

KW - Hypoxia

KW - MicroRNA

KW - Pseudohypoxia

KW - Renal cell carcinoma

KW - miR-126

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U2 - 10.1016/j.canlet.2017.02.025

DO - 10.1016/j.canlet.2017.02.025

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SN - 0304-3835

VL - 394

SP - 65

EP - 75

JO - Cancer Letters

JF - Cancer Letters

ER -

Pseudohypoxia induced by miR-126 deactivation promotes migration and therapeutic resistance in renal cell carcinoma

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