MiR-125a suppresses tumor growth, invasion and metastasis in cervical cancer by targeting STAT3

Zhongyi Fan; Hanzhi Cui; Xiaojie Xu; Zhi Lin; Xuelin Zhang; Lei Kang; Baiyu Han; Jing Meng; Zhifeng Yan; Xiang Yan; Shunchang Jiao

doi:10.18632/oncotarget.4457

MiR-125a suppresses tumor growth, invasion and metastasis in cervical cancer by targeting STAT3

Oncotarget. 2015 Sep 22;6(28):25266-80. doi: 10.18632/oncotarget.4457.

Authors

Zhongyi Fan¹, Hanzhi Cui², Xiaojie Xu³, Zhi Lin¹, Xuelin Zhang¹, Lei Kang⁴, Baiyu Han⁵, Jing Meng¹, Zhifeng Yan¹, Xiang Yan¹, Shunchang Jiao¹

Affiliations

¹ Department of Oncology, PLA General Hospital, Beijing, China.
² Department of Oncology, 309th Hospital of PLA, Beijing, China.
³ Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, China.
⁴ Department of Nuclear Medicine, Peking University First Hospital, Beijing, China.
⁵ Department of Endocrinology and Metablism, 264th Hospital of PLA, Shanxi, China.

Abstract

MiR-125a has been characterized as a tumor suppressor in several cancers. However, the role of miR-125a in cervical cancer is unknown. In this study, we found the expression of miR-125a was downregulated in cervical cancer patients, and negatively correlated with the tumor size, FIGO stage, and preoperative metastasis. Kaplan-Meier analysis showed that miR-125a expression predicted favorable outcome for cervical cancer patients. Dual luciferase assays identified the STAT3 gene as a novel direct target of miR-125a. Functional studies showed that miR-125a overexpression significantly suppressed the growth, invasion and epithelial-mesenchymal transition (EMT) of cervical cancer cells both in vitro and in vivo via decreasing STAT3 expression. Moreover, miR-125a conferred to G2/M cell cycle arrest, accompanied by inhibition of several G2/M checkpoint proteins. Mechanistically, inactivation of miR-125a during cervical carcinogenesis was caused by HPV suppression of p53 expression. Clinically, STAT3, the expression of which, predicted poorer outcome, was inversely correlated with miR-125a in cervical cancer. These data highlight the importance of miR-125a in the cell proliferation and progression of cervical cancer, and indicate that miR-125a may be a useful therapeutic target for cervical cancer.

Keywords: STAT3; cell growth; cervical cancer; metastasis; miR-125a.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3' Untranslated Regions
Adenocarcinoma / genetics
Adenocarcinoma / metabolism*
Adenocarcinoma / mortality
Adenocarcinoma / secondary
Adenocarcinoma / therapy
Adenocarcinoma / virology
Animals
Binding Sites
Carcinoma, Squamous Cell / genetics
Carcinoma, Squamous Cell / metabolism*
Carcinoma, Squamous Cell / mortality
Carcinoma, Squamous Cell / secondary
Carcinoma, Squamous Cell / therapy
Carcinoma, Squamous Cell / virology
Cell Movement*
Cell Proliferation*
Epithelial-Mesenchymal Transition
Female
G2 Phase Cell Cycle Checkpoints
Gene Expression Regulation, Neoplastic
HeLa Cells
Humans
Kaplan-Meier Estimate
Mice, Inbred BALB C
Mice, Nude
MicroRNAs / genetics
MicroRNAs / metabolism*
Middle Aged
Neoplasm Invasiveness
Neoplasm Staging
Papillomaviridae / pathogenicity
Protein Binding
STAT3 Transcription Factor / genetics
STAT3 Transcription Factor / metabolism*
Signal Transduction
Time Factors
Transfection
Treatment Outcome
Tumor Burden
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism
Uterine Cervical Neoplasms / genetics
Uterine Cervical Neoplasms / metabolism*
Uterine Cervical Neoplasms / mortality
Uterine Cervical Neoplasms / pathology
Uterine Cervical Neoplasms / therapy
Uterine Cervical Neoplasms / virology

Substances

3' Untranslated Regions
MIRN125 microRNA, human
MicroRNAs
STAT3 Transcription Factor
STAT3 protein, human
TP53 protein, human
Tumor Suppressor Protein p53