Overexpressed COL3A1 has prognostic value in human esophageal squamous cell carcinoma and promotes the aggressiveness of esophageal squamous cell carcinoma by activating the NF-κB pathway

Zhou, Jianfeng; Yang, Yu‐Shang; Zhang, Hanlu; Luan, Siyuan; Xiao, Xin; Li, Xiaokun; Fang, Pinhao; Shang, Qi‐Xin; Chen, Long-Qi; Zeng, Xiaoxi; Yuan, Yong

doi:10.1016/j.bbrc.2022.05.029

Cited by 12 publications

(8 citation statements)

References 23 publications

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“…In view of function, knocking down COL3A1 can lead to a potent repression of gastric tumorigenesis 27 ; COL3A1 downregulation is able to hinder breast cancer cell growth and invasiveness through PD-L1 11 ; inhibition of COL3A1 also impedes xenograft tumor growth and metastasis in esophageal squamous cell carcinoma. 28 These findings prove the tumor-promoting role of COL3A1 in these cancers. Importantly, in NSCLC, COL3A1 also modulates this disease progression by accelerating cancer cell growth and hindering apoptosis.…”

Section: Discussionmentioning

confidence: 59%

Role and mechanism of COL3A1 in regulating the growth, metastasis, and drug sensitivity in cisplatin-resistant non-small cell lung cancer cells

Ren,

Zhao,

Lai

2024

Cancer Biology & Therapy

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Non-small cell lung cancer (NSCLC) is among the most difficult malignancies to treat. Type III collagen (COL3A1) can affect the progression and chemoresistance development of NSCLC. We herein explored the mechanism that drives COL3A1 dysregulation in NSCLC. Potential RNA-binding proteins (RBPs) and transcription factors (TFs) that could bind to COL3A1 were searched by bioinformatics. mRNA expression was detected by quantitative PCR. Protein expression was evaluated using immunoblotting and immunohistochemistry. The effects of the variables were assessed by gauging cell growth, invasiveness, migratory capacity, apoptosis, and cisplatin (DDP) sensitivity. The direct YY1/COL3A1 relationship was confirmed by ChIP and luciferase reporter experiments. Xenograft experiments were done to examine COL3A1’s function in DDP efficacy. COL3A1 showed enhanced expression in DDP-resistant NSCLC. In H460/DDP and A549/DDP cells, downregulation of COL3A1 exerted inhibitory functions in cell growth, invasiveness, and migration, as well as promoting effects on cell DDP sensitivity and apoptosis. Mechanistically, ELAV-like RNA binding protein 1 (ELAVL1) enhanced the mRNA stability and expression of COL3A1, and Yin Yang 1 (YY1) promoted the transcription and expression of COL3A1. Furthermore, upregulation of COL3A1 reversed ELAVL1 inhibition- or YY1 deficiency-mediated functions in DDP-resistant NSCLC cells. Additionally, COL3A1 downregulation enhanced the anti-tumor efficacy of DDP in vivo. Our investigation demonstrates that COL3A1 upregulation, induced by both RBP ELAVL1 and TF YY1, exerts important functions in phenotypes of NSCLC cells with DDP resistance, offering an innovative opportunity in the treatment of drug-resistant NSCLC.

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Section: Discussionmentioning

confidence: 59%

Role and mechanism of COL3A1 in regulating the growth, metastasis, and drug sensitivity in cisplatin-resistant non-small cell lung cancer cells

Ren,

Zhao,

Lai

2024

Cancer Biology & Therapy

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“…Recent studies have highlighted the importance of one-carbon units derived from the mitochondria in fueling cytoplasmic reactions, where MTHFD1L serves as a key enzyme responsible for the final step of the reaction in the mitochondrial chamber, generating formate as a critical source of one-carbon donor molecules [26]. Elevated MTHFD1L expression has been associated with adverse clinical outcomes, increased cell proliferation, and enhanced cell migration in various cancer types, including colorectal [27], liver [28], bladder [29], thyroid [30], and esophageal [31] cancers. Conversely, the knockdown of MTHFD1L expression inhibited cancer cell growth and induced apoptosis in these malignancies.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, downregulation of MTHFD1L or use of the antifolate drug methotrexate effectively reduced nicotinamide adenine dinucleotide phosphate levels, leading to reactive oxygen species (ROS) accumulation, ROS-associated cell cycle delay, and hindered cell growth in MH-CC97L human hepatocellular carcinoma cells [28]. Mechanistic studies employing gene expression profiling have highlighted that ERK5 signaling is one of the most inhibited pathways in MTHFD1L-knockdown KYSE-150 human esophageal squamous cell carcinoma cells [31]. Notably, treatment with the highly selective ERK5 inhibitor (BIX 02189) rescued the proliferation and metastasis induced by MTHFD1L overexpression in esophageal cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Identifying the role of MTHFD1L in prostate cancer progression from genetic analysis and experimental validation

Tsai

2024

Am J Cancer Res

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One-carbon metabolism plays a crucial role in tumorigenesis as it supplies the one-carbon units necessary for nucleotide synthesis, epigenetic regulation, and redox metabolism, ensuring the rapid proliferation of cancer cells. However, their roles in prostate cancer progression remain poorly understood. In this study, we investigated the association between genetic variants in the one-carbon metabolism pathway and clinical outcomes in patients receiving androgen deprivation therapy for prostate cancer. The associations of 130 single-nucleotide polymorphisms located within 14 genes involved in the one-carbon metabolism pathway with cancer-specific survival (CSS), overall survival, and progression-free survival were assessed using Cox regression in 630 patients with prostate cancer. Subsequently, functional studies were performed using prostate cancer cell lines. After adjusting for covariates and multiple testing, MTHFD1L rs2073190 was found to be significantly associated with CSS (P = 0.000184). Further pooled analysis of multiple datasets demonstrated that MTHFD1L was upregulated in prostate cancer and increased MTHFD1L expression was positively correlated with tumor aggressiveness and poor patient prognosis. Functionally, MTHFD1L knockdown suppressed prostate cancer cell proliferation and colony formation. RNA sequencing and pathway analysis revealed that differentially expressed genes were predominantly enriched in the cell cycle pathway. In conclusion, genetic variants in MTHFD1L of one-carbon metabolism may serve as promising predictors, and our findings offer valuable insights into the underlying genetic mechanisms of prostate cancer progression.

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“…Expression alteration for those genes was maintained when cells were depleted of p53 or treated with 5-FU, suggesting that MDM2 W329G mutation deregulates the p53-independent function of MDM2, particularly on extracellular matrix modulation. Note that overexpression of C6orf15 [55], COL3A1 [56], MMP9 [57], PAPPA2 [58], RAB11FIP4 [59], and TGM2 [60] has been linked to and suggested as prognosis marker for various types of cancers.…”

Section: Discussionmentioning

confidence: 99%

Cancer-associated MDM2 W329G mutant attenuates ribosomal stress-mediated p53 responses to promote cell survival and glycolysis

Lien

2024

Am J Cancer Res

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Although amplification/overexpression is the predominant mechanism for the oncogenic properties of MDM2, an increasing number of MDM2 somatic missense mutations were identified in cancer patients with the recent advances in sequencing technology. Here, we characterized an MDM2 cancer-associated mutant variant W329G identified from a patient sample that contains a wild-type p53 gene. Trp329 is one of residues that were reported to be critical to MDM2's binding to ribosomal protein L11 (RPL11). We found that the MDM2 W329G mutant was resistant to the inhibitory effect of RPL11 on MDM2-mediated p53 ubiquitination and degradation, in line with its defect on RPL11 binding. Using isogenic U2OS cells with or without endogenous MDM2 W329G mutation, we demonstrated that the expression of classic p53 targets induced by ribosomal stress signals was reduced in mutant cells. RNA-seq analysis revealed that upon 5-FU treatment, the p53 response was significantly impaired. Also, the 5-FU-mediated repression of genes in cell cycle progression and DNA replication was diminished in W329G mutant-containing cells. Physiologically, U2OS W329G cells were more resistant to cell growth inhibition induced by ribosomal stress and exhibited higher glycolytic rates upon 5-FU treatment. Together, our data indicated that cancer-associated MDM2 W329G mutant attenuates ribosomal stress-mediated p53 responses to promote cell survival and glycolysis.

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Overexpressed COL3A1 has prognostic value in human esophageal squamous cell carcinoma and promotes the aggressiveness of esophageal squamous cell carcinoma by activating the NF-κB pathway

Cited by 12 publications

References 23 publications

Role and mechanism of COL3A1 in regulating the growth, metastasis, and drug sensitivity in cisplatin-resistant non-small cell lung cancer cells

Role and mechanism of COL3A1 in regulating the growth, metastasis, and drug sensitivity in cisplatin-resistant non-small cell lung cancer cells

Identifying the role of MTHFD1L in prostate cancer progression from genetic analysis and experimental validation

Cancer-associated MDM2 W329G mutant attenuates ribosomal stress-mediated p53 responses to promote cell survival and glycolysis

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