JUND/linc00976 promotes cholangiocarcinoma progression and metastasis, inhibits ferroptosis by regulating the miR-3202/GPX4 axis

Abstract

Long noncoding RNAs (lncRNAs) are a novel class of noncoding RNAs that have emerged as critical regulators and biomarkers in various cancers. Nevertheless, the expression profile and mechanistic function of lncRNAs in cholangiocarcinoma (CCA) remain unclear. Herein, we examined the expression levels of linc00976 in clinical specimens and cell lines using reverse transcription-quantitative PCR. In total, 50 patients with CCA were enrolled to analyze the correlation between linc00976 expression and clinical characteristics of CCA. Loss- and gain-of-function experiments were performed to investigate the biological effects of linc00976 on proliferation, ferroptosis, migration, and invasion of CCA cells in vitro and in vivo. In situ hybridization, RNA immunoprecipitation, bioinformatic databases, RNA pull-down assay, a dual-luciferase reporter assay, mRNA sequencing, chromatin immunoprecipitation–PCR, and rescue experiments were performed to elucidate the underlying mechanisms of linc00976-induced competitive endogenous RNA regulatory networks. We characterized a novel and abundant lncRNA, linc00976, that functions as a pro-oncogenic regulator of CCA progression. Compared with normal controls, linc00976 was dramatically upregulated in CCA tissue samples and cell lines. Patients with CCA exhibiting high linc00976 expression had a highly advanced clinical stage, substantial lymph node metastasis, and poor overall survival. Knockdown of linc00976 significantly repressed proliferation and metastasis and promoted ferroptosis of CCA cells both in vitro and in vivo, whereas linc00976 overexpression exerted the opposite effect. Mechanistically, linc00976 competitively interacted with miR-3202 to upregulate GPX4 expression, thus contributing to the malignant biological behavior of CCA cells. Moreover, we demonstrated that JUND specifically interacts with the linc00976 promoter and activates linc00976 transcription. Accordingly, JUND promotes linc00976 transcription, and linc00976 plays a crucial role in accelerating CCA tumorigenesis and metastasis and inhibiting ferroptosis by modulating the miR-3202/GPX4 axis. These findings suggest that targeting linc00976 may afford a promising therapeutic strategy for patients with CCA.

USP8 positively regulates hepatocellular carcinoma tumorigenesis and confers ferroptosis resistance through β-catenin stabilization

“…GPX4 activity is considered as the key biomarker to directly monitor ferroptosis. Decreased intracellular GPX4 activity or direct degradation of GPX4 can lead to increased iron-dependent reactive oxygen species, then induce ferroptosis [ 51 , 52 ]. Wnt/β-catenin signaling is a conserved signaling axis that participates in diverse physiological processes of tumor, it is one of the most attractive targets for cancer therapy.…”

FOXP3 promote the progression of glioblastoma via inhibiting ferroptosis mediated by linc00857/miR-1290/GPX4 axis

“…Similarly, Wang et al [8] suggested that linc00336 hindered ferroptosis in lung cancer cells through a competing endogenous RNA (ceRNA) mechanism, leading to increased cell metastasis. Furthermore, our previous study [9] revealed that linc00976 upregulated the expression of GPX4, thereby inhibiting ferroptosis and increasing cholangiocarcinoma cell proliferation and metastasis. Hence, the recognition of defense mechanisms employed by cancer cells to resist ferroptosis was helpful for enhancing cancer therapy.…”

Competing endogenous RNA networks and ferroptosis in cancer: novel therapeutic targets

“… Non-small cell lung cancer [ 136 ] GPX4-regulating ceRNAs Linc00976/miR-3202/GPX4 Negative Linc00976 sponges miR-3202, leading to GPX4 upregulation. Cholangiocarcinoma [ 137 ] HCG18/miR-450b-5p/GPX4 Negative HCG18 sponges miR-450b-5p, leading to GPX4 upregulation. Hepatocellular carcinoma [ 138 ] CircBLNK/miR-188-3p/GPX4 Negative CircBLNK sponges miR-188-3p, leading to GPX4 upregulation.…”

“…As an upregulated lncRNA in cholangiocarcinoma, linc00976 increased expression is associated with lymph node metastasis and inferior overall survival of affected patients. Besides stimulating ferroptosis, linc00976 knockdown decreases the proliferation and migration of cholangiocarcinoma cells via the linc00976/miR-3202/GPX4 axis [ 137 ]. It has been reported that HCG18 knockdown decreases cell proliferation, increases apoptosis, and enhances sorafenib resistance via activating ferroptosis in hepatocellular carcinoma; these effects are mediated via the HCG18/miR-450b-5p/GPX4 axis [ 138 ].…”