Exosomal lncRNA HCG18 contributes to cholangiocarcinoma growth and metastasis through mediating miR-424-5p/SOX9 axis through PI3K/AKT pathway

Abstract

Cholangiocarcinoma is a highly aggressive malignant tumor disease with the increasing incidence and mortality. It’s urgent to identify specific biomarkers for cholangiocarcinoma treatment and diagnosis. Recent studies have noted the importance of lncRNAs in cancer and the following downstream mechanism with miRNAs network has been a hotspot. This work aimed to discover the role of lncRNA HCG18 and its possible downstream mechanism in cholangiocarcinoma tumor progression. Initially, through bioinformatics tools, we observed abnormal expression of lncRNA HCG18 in cholangiocarcinoma. In vitro experiments like (CCK-8, EdU, colony formation, flow cytometry, transwell, wound healing assays) and animal study confirmed that lncRNA HCG18 served as a cancer-promoting gene, promoted cancer proliferation, migration and invasion abilities. Besides, we found cancer cell-secreted exosomes transitted HCG18 to surrounding tumor cells and accelerated tumor growth and metastasis. After that, we confirmed HCG18 directly interacted with miR-424-5p through FISH, RIP and dual luciferase reporter assays with negative modulation. The inhibition of miR-424-5p reversed the HCG18 knockdown induced suppression on cholangiocarcinoma cancer cells. More specific, miR-424-5p targeted to SOX9 contributed to cholangiocarcinoma growth and metastasis through mediating PI3K/AKT pathway. In conclusion, these findings provide solid evidence of lncRNAs/miRNAs regulation in cholangiocarcinoma progression.

Identification and analysis of MSC-Exo-derived LncRNAs related to the regulation of EMT in hypospadias

“…For example, exosomes secreted by polymorphonuclear neutrophils may affect the polarization of alveolar macrophages by transferring HCG18 and adsorbing miR-146b, thus resulting in acute pulmonary injury [ 34 ]. Exosome-derived lncRNA HCG18 could promote the growth and metastasis of cholangiocarcinoma cells through the miR-424-5p/SOX9 axis of the PI3K/AKT pathway [ 35 ]. Exosome-derived lncRNA HCG18 can up-regulate the expression of KLF4 and promote the polarization of M2 macrophages by sponging miR-875-3p in macrophages, thus regulating the progression of gastric cancer [ 36 ].…”

The role of lncRNA HCG18 in human diseases

“…SOX9 has been reported to promote tumor progression by promoting tumor cell invasion and EMT processes 94,95 . Knocking down HCG18 can upregulate the expression of miR‐424‐5p and downregulate the expression of SOX9, thereby inhibiting the growth, migration, invasion, and EMT process of cholangiocarcinoma cells 42 . This finding may provide new basis for the diagnosis of cholangiocarcinoma.…”

Nanotherapeutic approaches for delivery of long non-coding RNAs: an updated review with emphasis on cancer

“…miR-424-5p contributes to CCA growth and metastasis by mediating the miR-424-5p/SOX9 axis via PI3K/ AKT signalling. 165 CCA biomarkers are rarely examined, but this molecular mechanism may control tumor progression. As a result of their involvement in the progression of CCA and their potential as biomarkers, lncRNA research in CCA has been a focus.…”