Identification of N6-methylandenosine related lncRNA signatures for predicting the prognosis and therapy response in colorectal cancer patients

Zhiyong Li; Yang Liu; Huijie Yi; Ting Cai; Yunwei Wei

doi:10.3389/fgene.2022.947747

Identification of N6-methylandenosine related lncRNA signatures for predicting the prognosis and therapy response in colorectal cancer patients

Front Genet. 2022 Sep 30:13:947747. doi: 10.3389/fgene.2022.947747. eCollection 2022.

Authors

Zhiyong Li^{1

2

3}, Yang Liu², Huijie Yi^{4

5}, Ting Cai^{6

7}, Yunwei Wei^{1

2}

Affiliations

¹ Department of Oncological and Endoscopic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
² Pancreatic and Gastrointestinal Surgery Division, HwaMei Hospital, University of Chinese Academy of Science, Ningbo, China.
³ Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China.
⁴ Peking University School of Nursing, Beijing, China.
⁵ Respiratory and Critical Care Medicine, Peking University People's Hospital, Beijing, China.
⁶ Department of Experimental Medical Science, HwaMei Hospital,University of Chinese Academy of Sciences, Ningbo, China.
⁷ Key Laboratory of Diagnosis and Treatment of Digestive System Tumors, Ningbo, Zhejiang, China.

Abstract

Despite recent advances in surgical and multimodal therapies, the overall survival (OS) of advanced colorectal cancer (CRC) patients remains low. Thus, discerning sensitive prognostic biomarkers to give the optimistic treatment for CRC patients is extremely critical. N6-methyladenosine (m6A) and long noncoding RNAs (lncRNAs) play an important role in CRC progression. Nonetheless, few studies have focused on the impact of m6A-related lncRNAs on the prognosis, tumor microenvironment (TME) and treatment of CRC. In this study, 1707 m6A-related lncRNAs were identified through Pearson correlation analysis and Weighted co-expression network analysis (WGCNA) using The Cancer Genome Atlas (TCGA) cohort. Then, 28 m6A-related prognostic lncRNAs were screened by univariate Cox regression analysis, followed by identifying two clusters by consensus clustering analysis. A prognostic model consisted of 8 lncRNA signatures was constructed by the least absolute shrinkage and selection operator (LASSO). Kaplan-Meier curve analysis and a nomogram were performed to investigate the prognostic ability of this model. The risk score of prognostic model act as an independent risk factor for OS rate. Functional enrichment analysis indicated that lncRNA signatures related tumor immunity. The low-risk group characterized by increased microsatellite instability-high (MSI-H), mutation burden, and immunity activation, indicated favorable odds of OS. Moreover, the lncRNA signatures were significantly associated with the cancer stem cell (CSC) index and drug sensitivity. In addition, 3 common immune genes shared by the lncRNA signatures were screened out. We found that these immune genes were widely distributed in 2 cell types of TME. Finally, a ceRNA network was constructed to identify ZEB1-AS1 regulatory axis in CRC. We found that ZEB1-AS1 was significantly overexpressed in tumor tissues, and was related to the metastasis of EMT and the chemoresistance of 5-Fu in CRC. Therefore, our study demonstrated the important role of m6A-related lncRNAs in TME remodeling. Moreover, these results illustrated the levels of ZEB1-AS1 might be valuable for predicting the progression and prognosis of CRC, and further provided a new target for the diagnosis and treatment of CRC patients.

Keywords: 5-fluorouracil8; N6-methylandenosine2; colorectal cancer1; genetic alteration5; immune cell infiltration6; long non-coding RNA3; prognostic4; single-cell sequencing7.