International Journal of Biological Sciences

Impact factor

ISSN 1449-2288

News feeds of IJBS published articles
Manuscript login

open access Global reach, higher impact

Journal of Genomics in PubMed Central. Submit manuscript now...


International Journal of Medical Sciences

Journal of Cancer

Journal of Genomics


Journal of Bone and Joint Infection (JBJI)


Journal of Biomedicine

PubMed Central Indexed in Journal Impact Factor

Int J Biol Sci 2018; 14(9):1054-1066. doi:10.7150/ijbs.25349

Research Paper

CCL2-SQSTM1 positive feedback loop suppresses autophagy to promote chemoresistance in gastric cancer

Wenxia Xu1, Qi Wei1, Mengjiao Han2, Bingluo Zhou2, Hanying Wang2, Jianbing Zhang3, Qiang Wang4, Jie Sun1, Lifeng Feng1, Shouyu Wang4, Yang Ye5, Xian Wang2, Jianwei Zhou4, Hongchuan Jin1,✉

1. Labortaory of Cancer Biology, Key Laboratory of Biotherapy in Zhejiang, Sir Runrun Shaw hospital, Medical School of Zhejiang University, China
2. Department of Medical Oncology, Sir Runrun Shaw hospital, Medical School of Zhejiang University, China
3. Pathology Center, Shanghai General Hospital, Medical School of Shanghai Jiaotong University
4. Department of Molecular Cell Biology and Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China
5. Department of Preventive Medicine and Public Health Laboratory Science, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China


Chemotherapy is one of the most important approaches for the treatment of various cancers. However, tumor cells often develop resistance to chemotherapeutic drugs. The tumor microenvironment reconstituted by various cytokines secreted from immune cells was recently found to play important roles in affecting therapeutic response of tumor cells. Herein, we reported that tumor cells can secrete autocrine cytokines to confer chemoresistance by inactivating proapoptotic autophagy. Through cytokine screening, we found that drug resistant cancer cells secreted more CCL2 than drug sensitive cells. Such secreted CCL2 could not only maintain chemoresistance in drug-resistant cancer cells but also confer drug resistance to drug-sensitive cancer cells. CCL2 attenuated drug-induced cytotoxicity by activating PI3K-Akt-mTOR signaling to inhibit proapoptotic autophagy and increase SQSTM1 expression. CCL2 expression in primary carcinoma tissues also correlated well with SQSTM1 expression. Either CCL2 knock-down or autophagy induction successfully reversed drug resistance of tumor cells. Moreover, increased expression of SQSTM1 in turn activated CCL2 transcription via NF-κB signal pathway, representing a positive feedback loop to maintain drug resistance. Therefore, our results provided a new insight to understand drug resistance, and indicated the potential value of CCL2 as a biomarker and intervention target for chemotherapy resistance.

Keywords: CCL2, drug resistance, apoptosis, autophagy, gastric cancer

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( See for full terms and conditions.
How to cite this article:
Xu W, Wei Q, Han M, Zhou B, Wang H, Zhang J, Wang Q, Sun J, Feng L, Wang S, Ye Y, Wang X, Zhou J, Jin H. CCL2-SQSTM1 positive feedback loop suppresses autophagy to promote chemoresistance in gastric cancer. Int J Biol Sci 2018; 14(9):1054-1066. doi:10.7150/ijbs.25349. Available from