lncRNA RP11-147L13.8 suppresses metastasis and chemo-resistance by modulating the phosphorylation of c-Jun protein in GBC

Abstract

Long non-coding RNAs (lncRNAs) have been identified as critical contributors in tumor progression for many types of cancer. However, their functions in gallbladder cancer (GBC) have not been systematically clarified. In this study, the clinical significance, biological function, and underlying mechanism of lncRNA RP11-147L13.8 in GBC were investigated. The quantitative real-time PCR result indicated that lncRNA RP11-147L13.8 was found to be recurrently downregulated in GBC tumor samples. Kaplan-Meier analysis revealed that decreased lncRNA RP11-147L13.8 expression level was associated with poor survival of GBC patients (p = 0.025). Then, both in vitro and in vivo experiments elucidated that the overexpression of lncRNA RP11-147L13.8 suppressed the migration and invasion abilities of GBC cells and promoted the sensitivity to gemcitabine of GBC cells. Furthermore, we found that lncRNA RP11-147L13.8 physically interacted with c-Jun protein and decreased the phosphorylation on serine-73 (c-Jun-Ser73), which might cause the enhancement of the migration, invasion, and sensitivity to gemcitabine of GBC tumor cells. In conclusion, our study identified lncRNA RP11-147L13.8 as a promising prognostic indicator for patients with GBC, providing insights into the molecular pathogenesis of GBC. lncRNA RP11-147L13.8 is a potential therapeutic combination for gemcitabine in GBC treatment.

Update on Chemoresistance Mechanisms to First-Line Chemotherapy for Gallbladder Cancer and Potential Reversal Strategies

“… 25 , 41 GBC sensitivity to cisplatin was shown to increase when MiR-1207-5p expression decreased in the peripheral blood. 24 , 32 These findings suggest that hypermethylation of ELP5 and noncoding RNAs plays a role in regulating GBC-specific chemoresistance.…”

Long Noncoding RNA LINC00467: Role in Various Human Cancers

“…( Wu et al, 2018 ) A study on gallbladder cancer revealed that the lncRNA RP11-147L13.8 serves as a tumor-suppressing gene by interacting with c-Jun protein via binding to its bZIP domain (a DNA-binding and dimerization domain) and suppressing c-Jun-ser73 phosphorylation. ( Zheng et al, 2021 ) Interestingly, another study on gallbladder cancer found that HuR protein specifically binds with lncRNAs-HGBC within the 1759–1906 nt-long region and enhances the stabilization of lncRNAs-HGBC ( Hu et al, 2019 ) Moreover, the lncRNA AK137033 was found to interact with mRNA Sfrp2 and HuR, forming the AK137033-Sfrp2-HuR complex, which contributes to the inhibition of cardiac fibrosis. ( Hao et al, 2019 )…”

Prognostic and clinicopathological significance of transcription factor c-Jun in hypopharyngeal squamous cell carcinoma: a 3-year follow-up retrospective study

“…c-Jun, a common transcription factor, is a major component of the dimeric transcription factor activator protein-1 (AP-1) which is a paradigm for transcriptional response to extracellular signaling [ 4 , 5 ]. After stimulation, c-Jun can immediately express and generate transcription factors, regulate the transcription and expression of other genes, affect the growth, development and differentiation of normal cells, and lead to malignant transformation of cells [ 6 , 7 ]. Evidence for the role of c-Jun in cancer has been established by quantifying the amount of c-Jun from various primary cancers tissue samples [ 8 ].…”