Hypoxia-induced Long Non-coding RNA LSAMP-AS1 Regulates ceRNA Network to Predict Prognosis for Pancreatic Cancer

Abstract

Background: The limited efficacy of chemotherapy and immunotherapy for pancreatic cancer is thought to be largely influenced by the surrounding cancer microenvironment. The hypoxic microenvironment caused by insufficient local blood supply is very important. However, the method to assess the level of hypoxia in the microenvironment of pancreatic cancer (PC) remains unclear.

Methods: In our research, we downloaded transcriptomic and clinicopathological data from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). A prognostic model was developed using univariate and multivariate Cox regression. The ConsensuClusterPlus R package was used to consistently cluster PC samples through unsupervised clustering. Gene set variation analysis (GSVA) was performed to identify the different functional phenotypes. The CIBERSORT evaluated the infiltration status of immune cells. qRT-PCR was performed to detect the expression of genes in PC cells and tissues.

Results: A preliminary risk model was developed to reflect the hypoxic environment of pancreatic cancer. We found that a high hypoxia risk score indicated poor long-term survival and the presence of an immunosuppressive microenvironment. In addition, based on prognostic hypoxia-related genes, 177 PC samples were divided into two subtypes. Compared with cluster 2, cluster 1 was defined as the "hypoxic subgroup". The infiltration of CD8 T cells, activated memory CD4 T cells, naive B cells, memory B cells, plasma cells, and neutrophils were lower in cluster 1, suggesting that there was significant immunosuppression in cluster 1. Beyond that, we constructed a ceRNA regulatory network composed of differentially expressed lncRNA, miRNA, and mRNA. LSAMPAS1/ hsa-miR-129-5p/S100A2 has been identified as a key ceRNA network that regulates the hypoxic environment and the prognosis of PC. Notably, in our study, qRT-PCR revealed the relative expression of LSAMP-AS1 and S100A2 was significantly upregulated in PC cells and tissue.

Conclusion: The hypoxia-related prognostic risk model and core ceRNA network established in our study will provide a new perspective for exploring the carcinogenic mechanism and potential therapeutic targets of pancreatic cancer.

Keywords: Hypoxia; TCGA; carcinogenic; ceRNA; pancreatic cancer; prognosis.