Study on lncRNA-miRNA-mRNA interaction in Esophageal Squamous Cell Carcinoma

Abstract

Esophageal cancer is the sixth most fatal form of cancer. While the situation has enhanced in treatment and care, the number of people being affected by it also increase every year. The statistics show almost a six-fold elevation in the number of cases and this number is ever increasing in all parts of world  either in the form of squamous cell carcinoma ( dominant in Asian population) or adenocarcinoma (dominant in western population). To tackle this problem, new biomarkers are needed and improved therapeutic targets have to be studied. These biomarkers could help in predicting the potency of chemotherapy as often patients respond poorly to therapy because of resistance provided to the drugs by these molecules [1-2].

 Differential regulation of various lncRNAs in cancer has been studied previously and it has shown that deregulation of lncRNAs alters various cellular functions like angiogenesis, metastasis, tumor suppressor evasion, cell proliferation and many more [4]. miRNA is also involved in various pathways of cancer and can be correlated with the stage, type and other clinical aspects thus acting as a potential biomarker tool for diagnosis and prognosis of cancer [3]. While miRNA and lncRNA individually affect causation of cancer, but they also show interaction within each other and regulate functions of each other which in turn affect the biological processes altered in cancer cells. Various ways through which they interact with each other include acting as decay causing agents for each other, acting as suppressor and restricting binding to other molecules or acting as a reservoir [4]. In esophageal cancer, miRNAs can directly affect the regulation of a target mRNA in the signaling pathway, but lncRNAs often sponge miRNAs which in turn leads to metastasis and increased invasiveness and their interaction with each other further affects the axis of signaling, hitting single or multiple   cascading targets at a time throughout the cancer cells[11-12]. Not only this, various lncRNAs like DNM3OS,HOTAIR, PART1 to name a few, cause radioresistance or chemoresistance   in Esophageal cancer making the conditions severe[8-10]. Thus, targeting them directly or indirectly can help benefit patients suffering from esophageal cancer.

 In this study, we see the interaction between lncRNA-miRNA-mRNA in esophageal squamous cell carcinoma (ESCC). Here newly found lncRNAs and miRNAs can act as potential biomarkers and interacting mRNAs as putative targets. We identified differentially expressed lncRNAs (DELs), differentially expressed miRNAs (DEMs), differentially expressed genes (DEGs) from microarrays provided in Gene Expression Omnibus database with p-value<0.05 as significance criteria [Fig.2.(A,B),3.(A),4.(A)]. 17 up-regulated lncRNAs, 107 up-regulated and 103 down-regulated miRNAs, 11922 up-regulated and 12164 down-regulated significant genes, were predicted. Interactions among DELs, DEMs and DEGs wherein 26 deregulated miRNAs [Fig.3.(B)] interacting with 7 different up-regulated lncRNAs and, 469 up-regulated and 540 down-regulated genes [Fig.4.(B,C)] interacting with those miRNAs were procured.

For the very first time, lncRNAs like HAGLROS, C2orf27a and a few others which already show altered expression in other types of cancer were identified in microarray profiles of ESCC as well [5-7]. TCGA analysis of DELs confirmed overexpression [Fig.5.]. The interactions among DELs, DEMs and DEGs characterize the role of various molecules in ESCC tissue and how each one further targets other cascading molecules of the signaling pathways in which they participate are yet to be studied.