STING promotes proliferation and induces drug resistance in colorectal cancer by regulating the AMPK-mTOR pathway

Huihui Yao; Suo Wang; Xin Zhou; Jinbing Sun; Guoqiang Zhou; Diyuan Zhou; Guoliang Chen; Xinyu Shi; Junjie Chen; Bo Shi; Qingliang Tai; Xiuwei Mi; Liang Sun; Yizhou Yao; Songbing He

doi:10.21037/jgo-22-957

STING promotes proliferation and induces drug resistance in colorectal cancer by regulating the AMPK-mTOR pathway

J Gastrointest Oncol. 2022 Oct;13(5):2458-2471. doi: 10.21037/jgo-22-957.

Authors

Huihui Yao^#¹, Suo Wang^#^{1

2}, Xin Zhou³, Jinbing Sun², Guoqiang Zhou^#⁴, Diyuan Zhou^#¹, Guoliang Chen¹, Xinyu Shi¹, Junjie Chen¹, Bo Shi¹, Qingliang Tai¹, Xiuwei Mi¹, Liang Sun¹, Yizhou Yao¹, Songbing He¹

Affiliations

¹ Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China.
² Department of General Surgery, Changshu Hospital Affiliated to Soochow University, First People's Hospital of Changshu City, Changshu, China.
³ Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China.
⁴ Department of Gastrointestinal Surgery, Changshu No. 2 Hospital, Changshu, China.

^# Contributed equally.

Abstract

Background: In recent years, reports regarding stimulator of interferon genes (STING) and the progression of colorectal cancer (CRC) have emerged rapidly, yet their association remains controversial. This research was aimed to provide an insight into the prognostic biomarker and therapeutic target significance of STING in CRC.

Methods: CRC Cell lines of HCT116 and SW480, as well as 32 paired CRC specimens were chosen for this study. STING expressions were examined by immunohistochemistry to evaluate the correlation with clinicopathological factors. Data analysis of STING expressions in colon cancer and rectal cancer were performed using The Cancer Genome Atlas (TCGA) database. siRNA was transfected into cell lines for knocking down the expression of STING. Transwell assay was employed to evaluate cell migration and invasiveness. CCK-8 assay was used for assessing the change of cell proliferation. Drug sensitive test was involved to evaluate drug resistance of cell lines. Gene Set Enrichment Analysis (GSEA) was applied for exploring potential downstream mechanism of STING in CRC progression and Western blotting is used for mechanism validation.

Results: In the thirty-two paired CRC and adjacent normal tissues, we found a significant up-regulated in STING expression with immunohistochemical staining in cancer tissues compared with adjacent normal tissues (P<0.01), which was correlated with the tumor-node-metastasis (TNM) stage of patients (P=0.028). Meanwhile, GESA enrichment analysis indicated a remarkable change in mTOR signaling following STING regulation. In HCT116 and SW480 cell lines of CRC, When STING was down-regulated, its biological behavior of cell viability, cell invasion and drug sensitivity to 5-fluorouracil were significantly reduced (P<0.05), we also observed the up-regulation of P-AMPK (P<0.05) and down-regulation of p-mTOR (P<0.05).

Conclusions: STING expressions was significantly up-regulated in CRC tissues. Expression of STING was correlated with the TNM stage of patients. STING is found to promote cell proliferation, invasion ability and drug resistance mediating AMPK-mTOR signaling in CRC. STING could be a promising target for the sensitization of chemotherapy and inhibits CRC progression.

Keywords: Colorectal cancer (CRC); clinicopathological features; drug resistance; proliferation; stimulator of interferon genes (STING).