J Cancer 2020; 11(12):3634-3644. doi:10.7150/jca.42731

Research Paper

miR-365a-3p regulates ADAM10-JAK-STAT signaling to suppress the growth and metastasis of colorectal cancer cells

Yong-gang Hong1*, Cheng Xin1*, Hao Zheng2,3,4,5*, Zhi-ping Huang6*, Yuan Yang3,4,5, Ji-dian Zhou1, Xian-hua Gao1, Lun Hao7, Qi-zhi Liu1, Wei Zhang1✉, Li-qiang Hao1✉

1. Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University Shanghai, P.R. China, 200433
2. Department of Reproductive Heredity Center, Changhai Hospital, Second Military Medical University, Shanghai, 200433, People's Republic of China.
3. Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, 200438, People's Republic of China.
4. Key Laboratory of Signalling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai, 200438, People's Republic of China.
5. Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai, 200438, People's Republic of China.
6. Department of Hepatobiliary Surgery, General Hospital of Southern Theatre Command, Guangzhou 510010, People's Republic of China
7. Pella Christian High School, Iowa, United States of America.
*These authors contributed equally to this work

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Citation:
Hong Yg, Xin C, Zheng H, Huang Zp, Yang Y, Zhou Jd, Gao Xh, Hao L, Liu Qz, Zhang W, Hao Lq. miR-365a-3p regulates ADAM10-JAK-STAT signaling to suppress the growth and metastasis of colorectal cancer cells. J Cancer 2020; 11(12):3634-3644. doi:10.7150/jca.42731. Available from http://www.jcancer.org/v11p3634.htm

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Abstract

Purpose: MicroRNAs (miRNAs) are key regulators of the growth and development of a wide range of cancer types such as colorectal cancer (CRC). A number of previously studies have observed that the levels of miR-365a-3p expression are dysregulated in many cancers, but the specific role of this miRNA in CRC and its association with patient prognosis remains unclear.

Methods: The expression of miR-365a-3p in CRC tissues and cell lines was detected by Real-time Quantitative polymerase chain reaction (RT-qPCR), while the relationship between miR-365a-3p expression and clinicopathological characteristics was further analyzed. After increasing the expression of miR-365a-3p by plasmid transfection in CRC cells, we further investigated the cell proliferation, invasion and migration by cell counting kit-8 (CCK-8), and Transwell assays. Epithelial-mesenchymal transition (EMT) pathway was also measured by western blotting. In addition, the relationship among miR-365a-3p, ADAM10 and JAK in CRC, was explored by luciferase reporter assay.

Results: In the present study, we determined that CRC cells and clinical samples exhibited decreased miR-365a-3p expression, and this was associated with larger tumor size, lymph node metastasis, and local invasion. Patients with lower expression of miR-365a-3p had significantly decreased recurrence-free survival (RFS) and overall survival (OS) relative to those with higher levels of this miRNA. In a multivariate analysis, we confirmed that reduced miR-365a-3p levels were independently predictive of poorer CRC patient outcomes. In a functional study, we determined that elevated miR-365a-3p expression inhibited the ability of CRC cells to proliferate and metastasize in vitro and in vivo. We further identified ADAM10 as a direct miR-365a-3p target, resulting in the suppression of ADAM10 expression in cells expressing this miRNA and ADAM10 levels were in turn closely linked to JAK/STAT signaling.

Conclusion: Our study suggested the ability of miR-365a-3p to inhibit the progression of CRC at least in part via suppressing ADAM10 expression and associated JAK/STAT signaling, thus identifying this signaling axis as a possible prognostic and therapeutic target in CRC.

Keywords: miR-365a-3p, colorectal carcinoma, ADAM10, prognosis, biomarker