The Fra-1-miR-134-SDS22 feedback loop amplifies ERK/JNK signaling and reduces chemosensitivity in ovarian cancer cells

Jianmin Wu; Yimin Sun; Pei-Ying Zhang; Mengyao Qian; Hengchao Zhang; Xiao Chen; Di Ma; Yunsheng Xu; Xiaoming Chen; Kai-Fu Tang

doi:10.1038/cddis.2016.289

The Fra-1-miR-134-SDS22 feedback loop amplifies ERK/JNK signaling and reduces chemosensitivity in ovarian cancer cells

Cell Death Dis. 2016 Sep 29;7(9):e2384. doi: 10.1038/cddis.2016.289.

Authors

Jianmin Wu¹, Yimin Sun^{2

3}, Pei-Ying Zhang^{2

4}, Mengyao Qian¹, Hengchao Zhang^{2

4}, Xiao Chen^{2

4}, Di Ma^{2

4}, Yunsheng Xu^{2

5}, Xiaoming Chen^{2

6}, Kai-Fu Tang^{2

4}

Affiliations

¹ Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China.
² Institute of Translational Medicine, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang, China.
³ National Engineering Research Center for Beijing Biochip Technology, Beijing 102206, China.
⁴ Digestive Cancer Center, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang, China.
⁵ Department of Dermato-Venereology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang, China.
⁶ Department of Pediatric Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang, China.

Abstract

The Fra-1 transcription factor is frequently upregulated in multiple types of tumors. Here we found that Fra-1 promotes miR-134 expression. miR-134 activates JNK and ERK by targeting SDS22, which in turn induces Fra-1 expression and leads to miR-134 upregulation. In addition, miR-134 augmented H2AX S139 phosphorylation by activating JNK and promoted non-homologous end joining (NHEJ)-mediated DNA repair. Therefore, ectopic miR-134 expression reduced chemosensitivity in ovarian cancer cells. Furthermore, miR-134 promotes cell proliferation, migration and invasion of ovarian cancer cells, and enhances tumor growth in vivo. Of particular significance, both Fra-1 and miR-134 are upregulated in ovarian cancer tissues, and Fra-1 and miR-134 expression is positively correlated. High levels of miR-134 expression were associated with a reduced median survival of ovarian cancer patients. Our study revealed that a Fra-1-miR-134 axis drives a positive feedback loop that amplifies ERK/JNK signaling and reduces chemosensitivity in ovarian cancer cells.

MeSH terms

3' Untranslated Regions / genetics
Animals
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use*
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
DNA Repair / drug effects
Feedback, Physiological* / drug effects
Female
Gene Expression Regulation, Neoplastic / drug effects
Histones / metabolism
Humans
MAP Kinase Signaling System / drug effects
Mice, Nude
MicroRNAs / genetics
MicroRNAs / metabolism*
Neoplasm Invasiveness
Ovarian Neoplasms / drug therapy*
Ovarian Neoplasms / genetics
Ovarian Neoplasms / metabolism*
Phosphorylation / drug effects
Phosphoserine / metabolism
Protein Phosphatase 1 / metabolism*
Proto-Oncogene Proteins c-fos / metabolism*
Proto-Oncogene Proteins p21(ras) / metabolism
Transcription Factor AP-1 / metabolism
Treatment Outcome
Up-Regulation / drug effects

Substances

3' Untranslated Regions
Antineoplastic Agents
H2AX protein, human
Histones
MIRN134 microRNA, human
MicroRNAs
PPP1R7 protein, human
Proto-Oncogene Proteins c-fos
Transcription Factor AP-1
fos-related antigen 1
Phosphoserine
Protein Phosphatase 1
HRAS protein, human
Proto-Oncogene Proteins p21(ras)