miR-301a-3p induced by endoplasmic reticulum stress mediates the occurrence and transmission of trastuzumab resistance in HER2-positive gastric cancer |
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| Authors: | Jing Guo Xuxian Zhong Qinglin Tan Shengnan Yang Jiaqi Liao Jinke Zhuge Ziyang Hong Qiong Deng Qiang Zuo |
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| Institution: | 1.Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province China 510515 ;2.Department of Internal Medicine, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong Province China 510080 ;3.Department of Oncology, Dongguan People’s Hospital, Southern Medical University, Dongguan, Guangdong Province China 523059 |
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| Abstract: | Trastuzumab resistance negatively influences the clinical efficacy of the therapy for human epidermal growth factor receptor 2 (HER2) positive gastric cancer (GC), and the underlying mechanisms remain elusive. Exploring the mechanisms and finding effective approaches to address trastuzumab resistance are of great necessity. Here, we confirmed that endoplasmic reticulum (ER) stress-induced trastuzumab resistance by up-regulating miR-301a-3p in HER2-positive GC cells. Moreover, we elucidated that miR-301a-3p mediated trastuzumab resistance by down-regulating the expression of leucine-rich repeats and immunoglobulin-like domains containing protein 1 (LRIG1) and subsequently activating the expression of insulin-like growth factor 1 receptor (IGF-1R) and fibroblast growth factor receptor 1 (FGFR1) under ER stress. We also found that intercellular transfer of miR-301a-3p by exosomes disseminated trastuzumab resistance. The present study demonstrated that exosomal miR-301a-3p could serve as a non-invasive biomarker for trastuzumab resistance, which was maybe a novel potential therapeutic target to overcome trastuzumab resistance and improve the curative effect of trastuzumab in HER2-positive GC patients.Subject terms: Cancer therapeutic resistance, Gastric cancer |
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