A genetic variant conferred high expression of CAV2 promotes pancreatic cancer progression and associates with poor prognosis

Zhu, Ying; Tian, Jianbo; Peng, Xiaobo; Wang, Xiaoyang; Yang, Nan; Ying, Pingting; Wang, Haoxue; Li, Bin; Li, Yue; Zhang, Ming; Cai, Yimin; Lu, Zequn; Niu, Siyuan; Yao, Li; Zhong, Rong; Chang, Jiang

doi:10.1016/j.ejca.2021.04.008

Cited by 14 publications

(14 citation statements)

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“…In a study aiming to identify the functional genes and genetic variants associated with the prognosis of pancreatic ductal adenocarcinoma in 1070 patients, CAV2 was found to be upregulated and inversely associated with prognosis. Moreover, knockout of CAV2 suppressed tumor metastasis, and RNA-seq and bioinformatics analyses indicated that CAV2-related mRNAs were mainly enriched in pathways involved in metastasis [ 24 ]. However, this study did not further evaluate the mechanism by which CAV2 triggers metastasis.…”

Section: Discussionmentioning

confidence: 99%

CAV2 promotes the invasion and metastasis of head and neck squamous cell carcinomas by regulating S100 proteins

et al. 2022

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More than half of HNSCC patients are diagnosed with advanced disease. Locally advanced HNSCC is characterized by tumors with marked local invasion and evidence of metastasis to regional lymph nodes. CAV2 is a major coat protein of caveolins, important components of the plasma membrane. In this study, CAV2 was found to profoundly promote invasion and stimulate metastasis in vivo and in vitro. CAV2 was demonstrated to be a key regulator of S100 protein expression that upregulates the proteins levels of S100s, which promotes the invasion and migration and downregulates the expression of tumor suppressors. Mechanistically, CAV2 directly interacts with S100s in HNSCC cells, and CAV2 reduces S100A14 protein expression by promoting its ubiquitylation and subsequent degradation via the proteasome. Moreover, we discovered that CAV2 promotes the interaction between S100A14 and the E3 ubiquitin ligase TRIM29 and increases TRIM29 expression. Taken together, our findings indicate that CAV2 promotes HNSCC invasion and metastasis by regulating the expression of S100 proteins, presenting a novel potential target for anticancer therapy in HNSCC.

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Section: Discussionmentioning

confidence: 99%

CAV2 promotes the invasion and metastasis of head and neck squamous cell carcinomas by regulating S100 proteins

et al. 2022

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“…Recent tools such as GWAVA [ 68 ], DeepSEA [ 69 ], and Sei [ 70 ] use machine learning classification models to prioritize non-coding mutations. For example, based on a modified random forest algorithm, GWAVA prioritized five SNPs inside the 3’UTR of the caveolin 2 gene, CAV2 [ 71 ]. Through further investigations, one of the SNPs (rs10249656) was found to abolish an miRNA (miR-548s) binding site, leading to increased CAV2 expression, thus providing a plausible explanation for its association with pancreatic cancer [ 71 ].…”

Section: Strategies For Resolving the Gap In Functional Interpretatio...mentioning

confidence: 99%

“…For example, based on a modified random forest algorithm, GWAVA prioritized five SNPs inside the 3’UTR of the caveolin 2 gene, CAV2 [ 71 ]. Through further investigations, one of the SNPs (rs10249656) was found to abolish an miRNA (miR-548s) binding site, leading to increased CAV2 expression, thus providing a plausible explanation for its association with pancreatic cancer [ 71 ]. However, comparison across different machine learning models can become problematic since these tools uses different datasets to train their algorithms, which can affect the prioritized variants [ 72 ].…”

Section: Strategies For Resolving the Gap In Functional Interpretatio...mentioning

confidence: 99%

Interpretation of the role of germline and somatic non-coding mutations in cancer: expression and chromatin conformation informed analysis

Pudjihartono

Perry

et al. 2022

Clin Epigenet

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Background There has been extensive scrutiny of cancer driving mutations within the exome (especially amino acid altering mutations) as these are more likely to have a clear impact on protein functions, and thus on cell biology. However, this has come at the neglect of systematic identification of regulatory (non-coding) variants, which have recently been identified as putative somatic drivers and key germline risk factors for cancer development. Comprehensive understanding of non-coding mutations requires understanding their role in the disruption of regulatory elements, which then disrupt key biological functions such as gene expression. Main body We describe how advancements in sequencing technologies have led to the identification of a large number of non-coding mutations with uncharacterized biological significance. We summarize the strategies that have been developed to interpret and prioritize the biological mechanisms impacted by non-coding mutations, focusing on recent annotation of cancer non-coding variants utilizing chromatin states, eQTLs, and chromatin conformation data. Conclusion We believe that a better understanding of how to apply different regulatory data types into the study of non-coding mutations will enhance the discovery of novel mechanisms driving cancer.

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“…For example, CAV2 can promote renal cell carcinoma progression by influencing the EGFR/PI3K/Akt pathway [1] and CAV2 is associated with basal-like breast carcinoma and its poor prognosis [2]. The literature report suggests that CAV2 regulates various cancer cells' growth and biological activities [3].Further studies have shown that overexpressed CAV2 mechanically promotes PDAC progression and metastasis by disrupting focal adhesion (CCND1, IGTA1 and ZYX) and extracellular matrix (PLOD2, CAST and ITGA1) genes [4].Meanwhile, BRD4 can bind to the CAV2 promoter region and up-regulate the expression of CAV2, thereby promoting PDAC [5].CAV2 has also been shown to be a target of Mir-29a, and high CAV2 expression is responsible for poor prognosis [6].…”

Section: Ivyspringmentioning

confidence: 99%

CAV2 Regulates Mir-4723/Wnt7A Signalling Axis through Endocytosis and Epithelial-Mesenchymal Transition to Promote Proliferation, Invasion, and Metastasis of Pancreatic Cancer Cells

Li¹,

Guo²,

Song³

et al. 2022

J. Cancer

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Background: Pancreatic cancer is one of the most aggressive malignancies globally, with no improvement in the cure rates yet.Caveolin-2 (CAV2) has been repeatedly reported to play an important role in cellular transport and signalling and in exhibiting a pro-oncogenic response in a variety of tumours, although its specific action mechanisms in pancreatic cancer are not well documented. MiRNA is recognized as a therapeutic target for a variety of tumours, making it an important regulator of the Wnt/β-catenin signalling pathway. MiR-4723/Wnt7A constitutes an oncogenic signalling axis in pancreatic cancer by targeting and inhibiting Wnt7A through the activation of MiR4723, but its molecular action mechanism remains unexplored. Therefore, in the present study, we investigated the effect of CAV2 on the MiR-4723/Wnt7A pathway and its action mechanism. Methods: We employed TCGA, the GEO database for bioinformatics analysis, cell proliferation assay, wound healing assay, Transwell assay, colony-forming assay, qRT-PCR, and Western blotting to validate the cancer-promoting role of CAV2 in pancreatic cancer and to determine its potential target WNT7A. We then explored CAV2 as a positive regulator of the Wnt7A/β-catenin pathway through immunofluorescence assay, qRT-PCR, and Western blotting. Database analyses, CCK-8 and qRT-PCR revealed that MiR-4723 is an oncogene in pancreatic cancer. Luciferase assay and qRT-PCR revealed that MiR-4723 is a negative regulator of the Wnt7A/β-catenin pathway. To investigate the mechanism of CAV2 action on MiR-4723/Wnt7A, we detected the gene expression of CAV2 through qRT-PCR after MiR-4723 overexpression. Several genes related to endocytosis and epithelial-mesenchymal transition (EMT) were subsequently analysed through immunofluorescence, Western blotting, and qRT-PCR. Results: Overexpression of CAV2 promotes invasion, migration, cloning and metastasis of pancreatic cancer cells. Overexpression of MiR-4723 inhibits CAV2 expression. Here, we are the first to demonstrate that CAV2 exerts a pro-carcinogenic effect on pancreatic cancer through the activation of the Wnt7A/β-catenin signalling pathway. Conclusion: CAV2 can regulate the MiR-4723/Wnt7A signalling axis in pancreatic cancer cell lines by inhibiting endocytosis and promoting EMT, thereby fulfilling the mechanism pro-carcinogenic effects.

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A genetic variant conferred high expression of CAV2 promotes pancreatic cancer progression and associates with poor prognosis

Cited by 14 publications

References 37 publications

CAV2 promotes the invasion and metastasis of head and neck squamous cell carcinomas by regulating S100 proteins

CAV2 promotes the invasion and metastasis of head and neck squamous cell carcinomas by regulating S100 proteins

Interpretation of the role of germline and somatic non-coding mutations in cancer: expression and chromatin conformation informed analysis

CAV2 Regulates Mir-4723/Wnt7A Signalling Axis through Endocytosis and Epithelial-Mesenchymal Transition to Promote Proliferation, Invasion, and Metastasis of Pancreatic Cancer Cells

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