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CCN2-MAPK-Id-1 Loop Feedback Amplification is involved in Maintaining Stemness in Oxaliplatin-resistant Hepatocellular Carcinoma

ABSTRACT: Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Most patients are at an advanced stage at diagnosis, and are not eligible for curative therapy. Chemotherapy is an alternative treatment for advanced HCCs, but resistance is found in many patients. Understanding the underlying mechanisms in chemo-resistance is critical to further improve the efficacy of HCC treatment. In this study, we found that increased expression of Id-1 and CCN2 were closely related to oxaliplatin resistance in HCC. Upregulation of CCN2 and Id-1 was independently associated with shorter survival and increased recurrence in HCC patients, and significantly enhanced oxaliplatin resistance and promoted lung metastasis in vivo, whereas knock-down of their expression significantly reversed the chemo-resistance and inhibited HCC cell stemness. cDNA microarrays and PCR revealed that Id-1 and MAPK pathway were the downstream signaling of CCN2, and Id-1 could upregulate CCN2 in a positive feedback manner. Moreover, CCN2 significantly enhanced oxaliplatin resistance by activating the MAPK signaling pathway and upregulating Id-1 expression. Meanwhile, MAPK/Id-1 signaling was demonstrated as one of the most important autocrine signaling pathways regulated by CCN2 in oxaliplatin-resistant models, and combination with sorafenib could improve the efficacy of oxaliplatin in HCC. Conclusions: These findings suggest that CCN2-MAPK-Id-1 loop feedback amplification is involved in oxaliplatin-resistant HCC, and the combination of oxaliplatin with inhibitor of CCN2 or MAPK signaling could provide a promising approach to ameliorating HCC progression and oxaliplatin resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE124529 | GEO | 2019/01/02

REPOSITORIES: GEO

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CCN2-MAPK-Id-1 Loop Feedback Amplification is involved in Maintaining Stemness in Oxaliplatin-resistant Hepatocellular Carcinoma

Project description:CCN2-MAPK-Id-1 Loop Feedback Amplification is involved in Maintaining Stemness in Oxaliplatin-resistant Hepatocellular Carcinoma

| PRJNA512377 | ENA

Oxaliplatin resistance is enhanced by saracatinib via upregulation of ABCG1 and Wnt/β-catenin signaling in hepatocellular carcinoma

Project description:Background:Oxaliplatin-resistant hepatocellular carcinoma (HCC) is associated with increased insulin-like growth factor 1 (IGF1) paracrine signaling, and the IGF1 receptor can be downregulated by inhibition of Src kinases. Therefore, we sought to determine whether Src inhibition and oxaliplatin treatment exerted synergistic effects on HCC cell lines. Methods: The antitumor effects of combined treatment with saracatinib and oxaliplatin on proliferation were evaluated in HCC cells as well as in saracatinib- and oxaliplatin-resistant HCC cell lines using cell viability assays, plate colony formation assays, and cell cycle distribution detection. RNA sequencing was used to explore the resistance mechanism, and the effects on ABCG1 and Wnt signaling in oxaliplatin resistance were confirmed. Results: Chemotherapy with oxaliplatin and saracatinib individually induced strong anti-HCC effects, while combined or sequential treatment of HCC cells with these two drugs exhibited reduced efficacy compared to treatment with the single drugs. Furthermore, treatment with saracatinib caused oxaliplatin resistance. RNA sequencing revealed 458 genes that were altered by treatment with saracatinib and oxaliplatin. Of these, the gene encoding the ATP-binding cassette transporter G1 ABCG1 and Wnt-associated genes were significantly upregulated. Upregulation of ABCG1 and oxaliplatin resistance were associated with activation of Wnt signaling. Interference with ABCG1 expression or inhibition of Wnt signaling resulted in reversal of the saracatinib-induced oxaliplatin resistance in the HCC cell lines. Conclusions: These studies demonstrated that combined or sequential chemotherapy with oxaliplatin and saracatinib reduced antitumor efficacy, and this antagonism was attributed to the upregulation of ABCG1 and activation of Wnt signaling pathway by saracatinib.

2019-03-30 | GSE129071 | GEO

YTHDF3 improves translation initiation of mRNAs with N6-methyladenosine methylation at 5’ untranslated region by facilitating eIF2AK2 recruitment in oxaliplatin-resistant colorectal cancer - RNA-seq cell line comparison

2022-02-04 | E-MTAB-11322 | biostudies-arrayexpress

Transcriptomic changes associated with CCN2/CTGF deficiency in the mouse embryonic retina

Project description:The cellular communication network (CCN) 2, also known as CTGF, is a secreted matricellular protein with regulatory functions in vasoproliferative and fibrotic diseases. Although CCN2 functions extend to developmental processes, the impact of CCN2/CTGF expression, or lack thereof, during retinogenesis is unknown. Herein, we used bulk RNA-sequencing to determine the transcriptomic changes associated with global deletion of CCN2 in E18.5 mouse retinas. we show that CCN2 signals act on intrinsic signal transduction pathway genes and induce genetic reprogramming of retinal progenitor cells endowing these cells with neurogenic and gliogenic potentials.

2022-04-01 | GSE171232 | GEO

Comparative proteomics reveal elevated CCN2 in NGLY1 deficient cells

Project description:N-glycanase 1(NGLY1) catalyzes the removal of N-linked glycans from newly synthesized or misfolded protein to exert protein quality control function via the process of endoplasmic reticulum-associated degradation (ERAD). NGLY1 deficiency (OMIM 615273) is a newly diagnosed rare genetic disorder with ~60 patients worldwide to date. The affected individuals present a broad spectrum of clinical features, including developmental delay, seizures, muscle weakness, liver failure, and the reduced secretion of sweats and tears. Recent studies explored several possible molecular mechanisms of NGLY1 deficiency including in vivo proteostasis, mitochondrial homeostasis, innate immunity, water and ion transport, with the goal of linking these findings to the pathophysiology of the disease. This study focuses on the dysregulation of ERAD in NGLY1 deficiency. We demonstrate the abnormal accumulation of ERAD substrates in NGLY1 deficient cells. Comprehensive global quantitative proteomics discovered elevated levels of novel endogenous proteins in NGLY1 defective human and mouse cells. Further biological validation assays confirmed the altered abundance of several key candidates’ that were observed in the isobarically labeled proteomic experiments. CCN2 was selected for further analysis due to its high fold change in different cell models of NGLY1 deficiency. Functional assays show elevated CCN2 and over-stimulated TGF-β signaling in NGLY1 deficient cells. Given the important role of CCN2 and TGF-β pathway in mediating systemic fibrosis, we propose a potential link of increased CCN2 and TGF-β signaling to microscopic liver fibrosis in NGLY1 patients.

2021-12-21 | PXD026301 | Pride

Project description:Oxaliplatin as a first-line drug frequently causes the chemo-resistance on colorectal cancer (CRC). N6-methyladenosine (m6A) methylation has been largely acknowledged in multiple biological functions. However, the molecular mechanisms underlying the m6A methylation in modulating anticancer drug resistance in CRC are still obscure. In present study, RIP-seq was conducted to investigate the occupancy of N6-methyladenosine RNA binding protein 3 (YTHDF3) served as “readers” that can recognize m6A modification site in HCT116 cells with oxaliplatin resistance (HCT116R). Then, YTHDF3 was knockdown by siRNA in HCT116 cells with oxaliplatin resistance, and RIP-seq was further conducted to investigate m6A methylation of HCT116, HCT116R and HCT116R cells with YTHDF3 knockdown.

2022-02-04 | E-MTAB-11321 | biostudies-arrayexpress

CCN2 deficiency in smooth muscle cells triggers cell reprogramming and aggravates aneurysm development

Project description:Vascular smooth muscle cell (VSMC) phenotypic switching is widely recognized as a key mechanism responsible for the pathogenesis of several aortic diseases such as aortic aneurysm. Cellular communication network factor 2 (CCN2), often upregulated in human pathologies and animal disease models, exerts a myriad of context-dependent biological functions. However, current understanding of the role of SMC-CCN2 in SMC phenotypic switching and its function in the pathology of abdominal aortic aneurysm (AAA) is lacking. Here we report the effect of SMC-restricted CCN2 deficiency of hypercholesterolemic mice on gene expression in infrarenal aorta with or without angiotensin II (Ang II)-infusion.

2023-03-02 | GSE221399 | GEO

METTL3 Confers Oxaliplatin Resistance Through the Activation of G6PD-enhanced Pentose Phosphate Pathway in Hepatocellular Carcinoma

Project description:Oxaliplatin-based therapeutics is a widely used treatment approach for hepatocellular carcinoma (HCC) patients; however, drug resistance poses a significant clinical challenge. Epigenetic modifications have been implicated in the development of drug resistance. In our study, employing siRNA library screening, we identified that silencing the m6A writer METTL3 significantly enhanced the sensitivity to oxaliplatin in both in vivo and in vitro HCC models. Further investigations through combined RNA-seq and non-targeted metabolomics analysis revealed that silencing METTL3 impeded the pentose phosphate pathway (PPP), leading to a reduction in NADPH and nucleotide precursors. This disruption induced DNA damage, decreased DNA synthesis, and ultimately resulted in cell cycle arrest. Mechanistically, METTL3 was found to modify E3 ligase TRIM21 near the 3'UTR with N6-methyladenosine, leading to reduced RNA stability upon recognition by YTHDF2. TRIM21, in turn, facilitated the degradation of the rate-limiting enzyme of PPP, G6PD, through the ubiquitination-proteasome pathway. Importantly, high expression of METTL3 was significantly associated with adverse prognosis and oxaliplatin resistance in HCC patients. Notably, treatment with the specific METTL3 inhibitor, STM2457, significantly improved the efficacy of oxaliplatin. These findings underscore the critical role of the METTL3/TRIM21/G6PD axis in driving oxaliplatin resistance and present a promising strategy to overcome chemoresistance in HCC.

2024-08-23 | GSE241802 | GEO

YTHDF3 improves translation initiation of mRNAs with N6-methyladenosine methylation at 5’ untranslated region by facilitating eIF2AK2 recruitment in oxaliplatin-resistant colorectal cancer

2022-02-05 | E-MTAB-11323 | biostudies-arrayexpress

RNA-sequencing of CCN2 knockout and wild type mice following 4 hours after IRI

Project description:In order to identify major regulatory events in the immediate phase of renal IRI associated with CCN2, we performed full transcriptome RNA-sequencing on a cDNA library constructed from RNA extracted from samples of kidney cortex.

2021-10-28 | GSE186316 | GEO

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