Downregulation of AC092894.1 promotes oxaliplatin resistance in colorectal cancer via the USP3/AR/RASGRP3 axis
Zhijian Zheng,
Ming Wu,
Hongyan Li,
Wenxia Xu,
Mengxiang Yang,
Kailing Pan,
Yuqi Ni,
Ting Jiang,
Hongjuan Zheng,
Xiayun Jin,
Yanfei Zhang,
Linchao Ding,
Jianfei Fu
Affiliations
Zhijian Zheng
Department of Medical Oncology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine
Ming Wu
Department of Clinical Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine
Hongyan Li
Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University
Wenxia Xu
Department of Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine
Mengxiang Yang
Department of Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine
Kailing Pan
Department of Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine
Yuqi Ni
Department of Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine
Ting Jiang
Department of Nuclear Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine
Hongjuan Zheng
Department of Medical Oncology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine
Xiayun Jin
Department of Medical Oncology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine
Yanfei Zhang
Department of Pathology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine
Linchao Ding
Department of Scientific Research, Affiliated Jinhua Hospital, Zhejiang University School of Medicine
Jianfei Fu
Department of Medical Oncology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine
Abstract Background Oxaliplatin resistance is a complex process and has been one of the most disadvantageous factors and indeed a confrontation in the procedure of colorectal cancer. Recently, long non-coding RNAs (lncRNAs) have emerged as novel molecules for the treatment of chemoresistance, but the specific molecular mechanisms mediated by them are poorly understood. Methods The lncRNAs associated with oxaliplatin resistance were screened by microarray. lncRNA effects on oxaliplatin chemoresistance were then verified by gain- and loss-of-function experiments. Finally, the potential mechanism of AC092894.1 was explored by RNA pull-down, RIP, and Co-IP experiments. Results AC092894.1 representation has been demonstrated to be drastically downregulated throughout oxaliplatin-induced drug-resistant CRC cells. In vivo and in vitro experiments revealed that AC092894.1 functions to reverse chemoresistance. Studies on the mechanism suggested that AC092894.1 served as a scaffold molecule that mediated the de-ubiquitination of AR through USP3, thereby increasing the transcription of RASGRP3. Finally, sustained activation of the MAPK signaling pathway induced apoptosis in CRC cells. Conclusions In conclusion, this study identified AC092894.1 as a suppressor of CRC chemoresistance and revealed the idea that targeting the AC092894.1/USP3/AR/RASGRP3 signaling axis is a novel option for the treatment of oxaliplatin resistance.
