MiR-148a Functions as a Tumor Suppressor by Targeting CCK-BR via Inactivating STAT3 and Akt in Human Gastric Cancer

Beiqin Yu; Xin Lv; Liping Su; Jianfang Li; Yingyan Yu; Qinlong Gu; Min Yan; Zhenggang Zhu; Bingya Liu

doi:10.1371/journal.pone.0158961

MiR-148a Functions as a Tumor Suppressor by Targeting CCK-BR via Inactivating STAT3 and Akt in Human Gastric Cancer

PLoS One. 2016 Aug 12;11(8):e0158961. doi: 10.1371/journal.pone.0158961. eCollection 2016.

Authors

Beiqin Yu¹, Xin Lv^{1

2}, Liping Su¹, Jianfang Li¹, Yingyan Yu¹, Qinlong Gu¹, Min Yan¹, Zhenggang Zhu¹, Bingya Liu¹

Affiliations

¹ Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Department of Vascular Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Abstract

MicroRNAs (miRNAs) have been widely accepted as a class of gene expression regulators which post-translationally regulate protein expression. These small noncoding RNAs have been proved closely involved in the modulation of various pathobiological processes in cancer. In this research, we demonstrated that miR-148a expression was significantly down-regulated in gastric cancer tissues in comparison with the matched normal mucosal tissues, and its expression was statistically associated with lymph node metastasis. Ectopic expression of miR-148a inhibited tumor cell proliferation and migration in vitro, and inhibited tumor formation in vivo. Subsequently, we identified cholecystokinin B receptor (CCK-BR) as a direct target of miR-148a using western blot and luciferase activity assay. More importantly, siRNA-induced knockdown of CCK-BR elicited similar anti-oncogenic effects (decreased proliferation and migration) as those induced by enforced miR-148a expression. We also found that miR-148a-mediated anti-cancer effects are dependent on the inhibition of STAT3 and Akt activation, which subsequently regulates the pathways involved in cell proliferation and migration. Taken together, our results suggest that miR-148a serves as a tumor suppressor in human gastric carcinogenesis by targeting CCK-BR via inactivating STAT3 and Akt.

MeSH terms

Animals
Apoptosis
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism
Blotting, Western
Cell Movement
Cell Proliferation
Female
Gene Expression Regulation, Neoplastic*
Humans
Immunoenzyme Techniques
Lymphatic Metastasis
Male
Mice
Mice, Nude
MicroRNAs / genetics*
Middle Aged
Neoplasm Invasiveness
Neoplasm Staging
Prognosis
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins c-akt / metabolism
RNA, Messenger / genetics
Real-Time Polymerase Chain Reaction
Receptor, Cholecystokinin B / genetics
Receptor, Cholecystokinin B / metabolism*
Reverse Transcriptase Polymerase Chain Reaction
STAT3 Transcription Factor / antagonists & inhibitors*
STAT3 Transcription Factor / genetics
STAT3 Transcription Factor / metabolism
Stomach Neoplasms / genetics
Stomach Neoplasms / metabolism
Stomach Neoplasms / pathology*
Tumor Cells, Cultured
Xenograft Model Antitumor Assays

Substances

Biomarkers, Tumor
MIRN148 microRNA, human
MicroRNAs
RNA, Messenger
Receptor, Cholecystokinin B
STAT3 Transcription Factor
STAT3 protein, human
Proto-Oncogene Proteins c-akt

Grants and funding

This study was supported by grants from National Natural Science Foundation of China (Nos. 81172324, 81272749, 91229106, 81372187), Science and Technology Commission of Shanghai Municipality (Nos. 12XD1403700, 13ZR1425600), Key Projects in the National Science & Technology Pillar Program of China (No. 2014BAI09B03). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of manuscript.