Circular RNA hsa_circ_0001846 facilitates the malignant behaviors of pancreatic cancer by sponging miR-204-3p and upregulating KRAS expression

Xiaolei Ma; Haocheng Zhang; Luning Wang; Mengxing Cheng; Yanxin Jia; Di Feng; Yating Lei; Xinyu Li; Lina Ba; Na Song; Xinxia Yang; Lidan Bai; Ruipu Zhang; Wenxiao Xu; Guofen Qiao

doi:10.1038/s41420-023-01733-2

Circular RNA hsa_circ_0001846 facilitates the malignant behaviors of pancreatic cancer by sponging miR-204-3p and upregulating KRAS expression

Cell Death Discov. 2023 Dec 11;9(1):448. doi: 10.1038/s41420-023-01733-2.

Authors

Xiaolei Ma^#¹, Haocheng Zhang^#^{1

2}, Luning Wang^#^{1

3}, Mengxing Cheng¹, Yanxin Jia¹, Di Feng⁴, Yating Lei¹, Xinyu Li¹, Lina Ba¹, Na Song¹, Xinxia Yang¹, Lidan Bai^{1

5}, Ruipu Zhang^{1

5}, Wenxiao Xu^{6

7}, Guofen Qiao⁸

Affiliations

¹ Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150086, China.
² Department of Pharmacy, the Sixth Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
³ Department of pharmacy intravenous admixture services, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
⁴ Department of Pathology, Harbin Medical University Cancer Hospital, Harbin, 150086, China.
⁵ Department of Orthopedics, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
⁶ Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150086, China. wenxuhmu@outlook.com.
⁷ Department of Orthopedics, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China. wenxuhmu@outlook.com.
⁸ Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150086, China. qiaogf@hrbmu.edu.cn.

^# Contributed equally.

Abstract

Pancreatic cancer (PC) is mainly derived from the exocrine pancreatic ductal epithelial cells, and it is strongly aggressive malignant tumor. Due to its insidious onset and the lack of effective diagnostic biomarkers, PC currently remains one of the main causes of cancer-related mortality worldwide. Recent studies have found that hsa_circ_0001846 is involved in the progression of multiple cancers and has the potential to become biomarkers, but its function and mechanism in PC remains unclear. We found by qRT-PCR experiments that hsa_circ_0001846 was upregulated in PC cells and tissues, while circBase, Sanger sequencing, agarose gel electrophoresis and FISH experiments identified the splicing site, ring structure and cellular localization of hsa_circ_0001846. Various functional experiments by using the construction of small interfering RNA targeting hsa_circ_0001846 and overexpression plasmid demonstrated that hsa_circ_0001846 promoted the proliferation, migration and invasion of PC cells. Moreover, the tumor weight and volume of nude mice were significantly reduced after the stable knockdown of hsa_circ_0001846. In the mechanism exploration, RNA pull-down experiments and dual-luciferase experiments helped us to determine that hsa_circ_0001846 regulated the KRAS expression by sponging miR-204-3p in PC, thus playing a pro-cancer role. In this study, the effect of miR-204-3p on PC was also explored for the first time, and we found that knockdown of miR-204-3p reversed the tumor suppressive effect caused by silencing hsa_circ_0001846, and silencing KRAS also rescued the pro-cancer effect caused by overexpression of hsa_circ_0001846. In conclusion, our study revealed the pro-cancer role of hsa_circ_0001846 in PC, and for the first time identified the mechanism that hsa_circ_0001846 regulated KRAS by sponging miR-204-3p to promote PC progression and had the potential to become a cancer biomarker.