Tumor-Promoting Actions of HNRNP A1 in HCC Are Associated with Cell Cycle, Mitochondrial Dynamics, and Necroptosis

Zhao, Biao; Lv, Xiaochen; Zhao, Xiaoqi; Maimaitiaili, Subinuer; Zhang, Yuheng; Su, Ke; Yu, Hang; Liu, Cheng; Qiao, Tong

doi:10.3390/ijms231810209

Cited by 11 publications

(5 citation statements)

References 45 publications

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“…Dysregulation of hnRNPA1 has been associated with various diseases, including cancer [ 38 ]. For example, hnRNPA1 was overexpressed in lung carcinoma, GC, and colorectal cancer [ 39 ] and has been correlated with poor prognosis in hepatocellular carcinoma and breast cancer [ 40 , 41 ]. In this study, GC patients with high levels of hnRNPA1 had unfavorable overall survival in TCGA database, and upregulation of hnRNPA1 protein expression was observed in OIP5-AS1-overexpressing GC cells.…”

Section: Discussionmentioning

confidence: 99%

N6-methyladenosine modification of OIP5-AS1 promotes glycolysis, tumorigenesis, and metastasis of gastric cancer by inhibiting Trim21-mediated hnRNPA1 ubiquitination and degradation

Xie,

Liu,

et al. 2023

Gastric Cancer

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Background Opa-interacting protein 5 antisense transcript 1 (OIP5-AS1) has been demonstrated to play vital roles in development and progression of tumors such as gastric cancer (GC). However, the detailed molecular mechanism of OIP5-AS1 has not been completely elucidated. Our study aimed to investigate the role and the epigenetic regulation mechanism of OIP5-AS1 in GC. Methods OIP5-AS1 expression in GC tissues was detected by RT-qPCR. Loss- and gain-of-function experiments were conducted to assess the biological function of OIP5-AS1 in vitro and in vivo. The interaction of OIP5-AS1 with insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) or heterogeneous nuclear nucleoprotein A1 (hnRNPA1) was verified by bioinformatics analysis, RNA pull-down assays, and RNA immunoprecipitation assays. Results In this study, we identified that OIP5-AS1 is specifically overexpressed in GC tumor tissues and cell lines and correlated with a poor prognosis. The loss of OIP5-AS1 suppressed the proliferation, migration, invasion, epithelial–mesenchymal transition (EMT), and glycolysis of GC cells, but the ectopic expression of OIP5-AS1 had the opposite impact. Meanwhile, knockdown of OIP5-AS1 inhibited tumor growth in patient-derived xenograft models, as well as repressed tumor metastasis. Mechanistically, IGF2BP3 could bind to OIP5-AS1 by N6-methyladenosine (m6A) modification sites on OIP5-AS1, thereby stabilizing OIP5-AS1. Moreover, OIP5-AS1 prevented Trim21-mediated ubiquitination and degradation of hnRNPA1, stabilizing hnRNPA1 protein and promoting the malignant progression of GC by regulating PKM2 signaling pathway. Conclusions In conclusion, this study highlighted that OIP5-AS1 is an oncogenic m6A-modified long non-coding RNA (lncRNA) in GC and that IGF2BP3/OIP5-AS1/hnRNPA1 axis may provide a potential diagnostic or prognostic target for GC.

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Section: Discussionmentioning

confidence: 99%

N6-methyladenosine modification of OIP5-AS1 promotes glycolysis, tumorigenesis, and metastasis of gastric cancer by inhibiting Trim21-mediated hnRNPA1 ubiquitination and degradation

Xie,

Liu,

et al. 2023

Gastric Cancer

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“…Abnormal RNA metabolism may have serious consequences for a variety of diseases due to abnormal regulation of RNAbinding proteins (Feng et al, 2022). In fibroblasts (Shimada et al, 2009) and hepatocellular carcinoma (Zhao et al, 2022), downregulation of hnRNP A1 accelerates cellular senescence, and hnRNP A1 expression gradually decreases to undetectable levels during fibroblast senescence (Wang et al, 2016). Aging is the most common risk factor in AD (Li et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Suppression of hnRNP A1 binding to HK1 RNA leads to glycolytic dysfunction in Alzheimer’s disease models

Ji,

Liu,

Wei

et al. 2023

Front. Aging Neurosci.

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ObjectiveTo investigate the mechanism of RNA-binding protein hnRNP A1 in mouse hippocampal neurons (HT22) on glycolysis.MethodsRIP and CLIP-qPCR were performed by HT22 in vitro to observe the mechanism of HNRNP-A1 regulating the expression of key proteins in glycolysis. The RNA binding domain of hnRNP A1 protein in HT22 was inhibited by VPC-80051, and the effect of hnRNP A1 on glycolysis of HT22 was observed. Lentivirus overexpression of HNRNP-A1 was used to observe the effect of overexpression of HNRNP-A1 on glycolysis of Aβ25–35-injured HT22. The expression of hnRNP A1 in brain tissues of wild-type mice and triple-transgenic (APP/PS1/Tau) AD mice at different ages was studied by Western blot assay.ResultsThe results of RIP experiment showed that hnRNP A1 and HK1 mRNA were significantly bound. The results of CLIP-qPCR showed that hnRNP A1 directly bound to the 2605-2821 region of HK1 mRNA. hnRNP A1 inhibitor can down-regulate the expression of HK1 mRNA and HK1 protein in HT22 cells. Overexpression of hnRNP A1 can significantly reduce the toxic effect of Aβ25–35 on neurons via the hnRNP A1/HK1/ pyruvate pathway. In addition, inhibition of HNRNP-A1 binding to amyloid precursor protein (APP) RNA was found to increase Aβ expression, while Aβ25–35 also down-regulated HNRNP-A1 expression by enhancing phosphorylation of p38 MAPK in HT22. They interact to form bidirectional regulation, further down-regulating the expression of hnRNP A1, and ultimately aggravating glycolytic dysfunction. Protein immunoblotting showed that hnRNP A1 decreased with age in mouse brain tissue, and the decrease was greater in AD mice, suggesting that the decrease of hnRNP A1 may be a predisposed factor in the pathogenesis of AD.

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“…A recent study has found that, as the liver progressively ages, necroptosis increases, which in turn continuously exacerbates chronic liver inflammation, thus exacerbating the HCC transition ( 157 ). This necroptosis-mediated liver inflammation process may be prevented by β-carotene and heterogeneous nuclear ribonucleoprotein A1 ( 158 , 159 ). In addition, excess sorbitol dehydrogenase (SORD) in HCC cells could inhibit tumor growth and stemness by enhancing necroptosis signaling, and treatment with human recombinant SORD controlled HCC cell growth and regulated macrophage polarization in the tumor microenvironment ( 160 ).…”

Section: Necroptosis In Hccmentioning

confidence: 99%

Ferroptosis, pyroptosis and necroptosis in hepatocellular carcinoma immunotherapy: Mechanisms and immunologic landscape (Review)

Liu,

Yu,

Yan

et al. 2024

Int J Oncol

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Hepatocellular carcinoma (HCC), one of the leading causes of cancer-related mortality worldwide, is challenging to identify in its early stages and prone to metastasis, and the prognosis of patients with this disease is poor. Treatment options for HCC are limited, with even radical treatments being associated with a risk of recurrence or transformation in the short term. Furthermore, the multi-tyrosine kinase inhibitors approved for first-line therapy have marked drawbacks, including drug resistance and side effects. The rise and breakthrough of immune checkpoint inhibitors (ICIs) have provided a novel direction for HCC immunotherapy but these have the drawback of low response rates. Since avoiding apoptosis is a universal feature of cancer, the induction of non-apoptotic regulatory cell death (NARCD) is a novel strategy for HCC immunotherapy. At present, NARCD pathways, including ferroptosis, pyroptosis and necroptosis, are novel potential forms of immunogenic cell death, which have synergistic effects with antitumor immunity, transforming immune 'cold' tumors into immune 'hot' tumors and exerting antitumor effects. Therefore, these pathways may be targeted as a novel treatment strategy for HCC. In the present review, the roles of ferroptosis, pyroptosis and necroptosis in antitumor immunity in HCC are discussed, and the relevant targets and signaling pathways, and the current status of combined therapy with ICIs are summarized. The prospects of targeting ferroptosis, pyroptosis and necroptosis in HCC immunotherapy are also considered.

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Tumor-Promoting Actions of HNRNP A1 in HCC Are Associated with Cell Cycle, Mitochondrial Dynamics, and Necroptosis

Cited by 11 publications

References 45 publications

N6-methyladenosine modification of OIP5-AS1 promotes glycolysis, tumorigenesis, and metastasis of gastric cancer by inhibiting Trim21-mediated hnRNPA1 ubiquitination and degradation

N6-methyladenosine modification of OIP5-AS1 promotes glycolysis, tumorigenesis, and metastasis of gastric cancer by inhibiting Trim21-mediated hnRNPA1 ubiquitination and degradation

Suppression of hnRNP A1 binding to HK1 RNA leads to glycolytic dysfunction in Alzheimer’s disease models

Ferroptosis, pyroptosis and necroptosis in hepatocellular carcinoma immunotherapy: Mechanisms and immunologic landscape (Review)

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