LINC00365 promotes miR-221-5p to inhibit pyroptosis via Dicer in colorectal cancer

Abstract

Pyroptosis, a newly discovered form of programmed cell death, is involved in the occurrence, development and drug resistance of a variety of tumors and has attracted increasing attention in recent years. LINC00365 is a novel lncRNA that has rarely been reported before. We previously reported that LINC00365 expression in colorectal cancer is closely associated with poor patient outcomes. Additionally, LINC00365 was confirmed to be positively correlated with miR-221-5p, and miR-221-5p is negatively correlated with gasdermin-D (GSDMD) in colorectal cancer tissues. Bioinformatics analysis and luciferase reporter gene experiments revealed that GSDMD is the target gene of miR-221-5p. Cell function experiments and nude mouse tumor transplantation assays confirmed that LINC00365 could regulate the expressions of pyroptosis-related proteins such as Caspase-1, Caspase-11, NLRP3 and GSDMD. RNA pulldown and RNA immunoprecipitation experiments further elucidated the mechanism by which LINC00365 regulates miR-221-5p. In the present study, we observe that LINC00365 promotes the expression of miR-221-5p by binding to the Dicer enzyme to inhibit GSDMD and plays an antipyroptotic role. Our findings suggest that LINC00365 may serve as a molecular biomarker for estimating the prognosis of patients with colorectal cancer and as a potential therapeutic target for colorectal cancer.

1. Introduction

Colorectal cancer (CRC) is one of the most common malignancies of the digestive tract. The latest global cancer statistics released by the American Cancer Society (ACS) show that CRC, with an incidence of 6.1% and a mortality of 9.2%, ranks as the third most common neoplasm in men and the second most common in women. Although the overall incidence of CRC tends to decline, this tumor appears to be prevalent in the American young population annually [1,2]. In China, the incidence and detection rate of CRC have increased annually, and the growth trend is faster than that in the populations of Europe and the United States. Terribly, this tumor tends to affect younger people [3,4]. Therefore, seeking an effective diagnosis for CRC at an early stage and timely treatment are highly important for relieving economic and social pressure as well as improving population health.

CRC commonly progresses from local lesions to distant metastases. At present, the clinical treatment of this disease generally relies on radical surgery. However, the incidence of postoperative liver metastases can be as high as 30% to 50%, and liver involvement precedes in 20% to 40% of patients upon clinical diagnosis, which results in the inability of surgical treatment for some patients [5,6]. At present, effective therapies to improve the prognosis of patients with colorectal cancer are still lacking. Thus, systematically exploring the specific molecular biological mechanisms involved in the development of CRC will contribute to a better understanding of the pathogenesis of this neoplasm and the discovery of new therapeutic targets. Tumorigenesis is widely believed to overcome the boundaries of programmed death through a complex set of mechanisms. Programmed cell death is known as apoptosis. Recently, with increasing research, many methods of programmed cell death (PCD), including apoptosis, pyroptosis, autophagy and ferroptosis, [7] have been identified.