The Fra-1-miR-134-SDS22 feedback loop amplifies ERK/JNK signaling and reduces chemosensitivity in ovarian cancer cells.
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.
Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China.
Jianmin
J
Wu
Institute of Translational Medicine, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang, China.|National Engineering Research Center for Beijing Biochip Technology, Beijing 102206, China.
Yimin
Y
Sun
Institute of Translational Medicine, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang, China.|Digestive Cancer Center, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang, China.
Pei-Ying
PY
Zhang
Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China.
Mengyao
M
Qian
Institute of Translational Medicine, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang, China.|Digestive Cancer Center, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang, China.
Hengchao
H
Zhang
Institute of Translational Medicine, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang, China.|Digestive Cancer Center, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang, China.
Xiao
X
Chen
Institute of Translational Medicine, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang, China.|Digestive Cancer Center, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang, China.
Di
D
Ma
Institute of Translational Medicine, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang, China.|Department of Dermato-Venereology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang, China.
Yunsheng
Y
Xu
Institute of Translational Medicine, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang, China.|Department of Pediatric Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang, China.
Xiaoming
X
Chen
Institute of Translational Medicine, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang, China.|Digestive Cancer Center, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang, China.
Kai-Fu
KF
Tang
D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D025461:Feedback, Physiological / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D054645:Protein Phosphatase 1 / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects; D000099169:Fos-Related Antigen 1
D020413:3' Untranslated Regions; D000970:Antineoplastic Agents; D006657:Histones; D035683:MicroRNAs; D010768:Phosphoserine; D054645:Protein Phosphatase 1; D016760:Proto-Oncogene Proteins c-fos; D016283:Proto-Oncogene Proteins p21(ras); D018808:Transcription Factor AP-1; D000099169:Fos-Related Antigen 1; C468783:H2AX protein, human; C569273:MIRN134 microRNA, human; C509751:PPP1R7 protein, human; C501009:HRAS protein, human
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