The role of XBP-1-mediated unfolded protein response in colorectal cancer progression-a regulatory mechanism associated with lncRNA-miRNA-mRNA network

Abstract

Background We aim to identify the expression and analyze the molecular action of dysregulated lncRNA-miRNA mediated by XBP-1 in colorectal cancer (CRC). Methods Here, we identified XBP-1-mediated dysregulated lncRNAs and miRNAs in CRC by bioinformatics analysis. The expression level of lncRNAs and miRNA was measured using quantitative real time PCR, and the expression of XBP-1, as well as apoptosis-related proteins, were detected by western blot. CCK-8 and TUNEL assays were performed to determine cell proliferation and apoptosis, respectively. Luciferase reporter assay was conducted to verify the binding relationship among lncRNA-miRNA-XBP-1. BALB/c nude mice were inoculated subcutaneously with HCT116 cells to establish tumor-bearing mice model. Histological analysis was carried out by HE staining and immunohistochemical staining. Results Six downregulated lncRNAs (SLFNL1-AS1, KCNQ1OT1, NEAT1, XIST, AC016876.2, AC026362.1), four dysregulated miRNAs (miR-500a-3p, miR-370-3p, miR-2467-3p, miR-512-3p) and upregulated XBP-1 were identified in CRC cell lines. Gain- and loss-of-function experiments showed that overexpression of KCNQ1OT1/XIST promoted cell proliferation and suppressed cell apoptosis. In addition, overexpression of KCNQ1OT1/XIST partly abolished the inhibitory effects of XBP-1u knockdown or tunicamycin, an activator of endoplasmic reticulum stress, on CRC cell viability loss and apoptosis. Furthermore, KCNQ1OT1/XIST aggravated tumor growth in vivo by regulating endoplasmic reticulum stress and cell apoptosis. Conclusions This study has constructed lncRNA-miRNA-mRNA networks based on XBP-1 in CRC, and disclosed the regulatory mechanism of action, providing a set of pivotal biomarkers for future molecular investigation and targeted treatment of CRC.

The role of endoplasmic reticulum stress in the regulation of long noncoding RNAs in cancer

“…In another part of the study, increased expression of KCNQ1OT1/XIST showed the effects of inhibiting XBP1 on the loss of viability of colorectal cancer cells and inhibition of apoptosis. Overall, Y. Wang et al (2021) in this study found that KCNQ1OT1/XIST accelerated tumor growth by regulating ER stress and cellular apoptosis in colorectal cancer in vitro and in vivo.…”

“…In a recent study, the role of XBP1 in regulating the expression of lncRNA networks in colorectal cancer was investigated (Ebrahimi, Rezanejad, et al, 2022; Y. Wang et al, 2021). With increasing XBP1 expression in colorectal cancer cell lines, six lncRNAs including NEAT1, SLFNL1‐AS1, XIST, KCNQ1OT1, AC026362.1, and AC016876.2 showed decreased expression.…”

The lncRNAs at X Chromosome Inactivation Center: Not Just a Matter of Sex Dosage Compensation

“…In fact, growing evidence linking pathological conditions to lncRNAs and their regulatory network is emerging, especially in cancer development and progression, with important implications in diagnostics and therapeutics. Specifically, different studies report the correlation of XIST expression with prognosis such as in the case of colon and gastric cancer, glioma and cervical and ovarian cancer [ 65 , 66 , 67 , 68 , 69 , 76 , 77 , 78 , 79 , 83 , 84 , 85 , 86 ] or FTX expression and gastric cancer prognosis [ 179 ] or JPX expression and poor survival of lung cancer patients [ 188 , 189 ]; probably, combination of the expression values of more than one RNA molecule involved in the same regulatory axis could enhance the diagnostic power, e.g., making it possible to stratify the patients according tumor stage, favorable/unfavorable outcome and even therapy effectiveness. Finally, understanding the versatility of RNA biology has become a stepping stone for RNA therapeutics that has definitely demonstrated its power [ 13 ].…”

“…Intriguingly, the XIST ceRNA activity is also involved in chemoresistance: as an example, XIST competes with serum and glucocorticoid-inducible kinase 1 (SGK1) by sponging the shared miR-124, and thus enhancing doxorubicin resistance [ 66 ]. Recently, complex lncRNA/miRNA/mRNA networks based on XIST/miR-500a-3p, miR-370-3p, miR-2467-3p, miR-512-3p/XBP have been demonstrated to promote cell proliferation and aggravated tumor growth in vivo by regulating endoplasmic reticulum stress response and cell apoptosis [ 67 ].…”

Targeting lncRNA/Wnt axis by flavonoids: A promising therapeutic approach for colorectal cancer

“…At the post‐transcriptional level, lncRNAs could act as molecular sponges that function as competing endogenous RNAs (ceRNAs) by competitively occupying the shared binding sequences of miRNAs, thereby sequestering miRNAs and altering the expression of their downstream target genes. Mechanistically, CRC‐related lncRNAs proved to be activated or inhibited through epigenetic modification, lncRNA‐miRNA‐mRNA, lncRNA‐ceRNA, lncRNA‐protein, regulation of Wnt/β‐Catenin signaling pathway (Li, Mu, Shi, & Xin, 2021; Qi, Lin, Liu, Chen, & Shen, 2020; Wang, Zhang, & Zheng, 2021). Functionally, lncRNAs exhibit four main regulatory roles, namely, signal, decoy, guide, and scaffold to regulate gene expression (Ming, Li, Zhou, Goel, & Huang, 2021).…”