Oncogenic potential of BEST4 in colorectal cancer via activation of PI3K/Akt signaling

He, Xiaoshun; Ye, Wen-Long; Zhang, Yu-Juan; Yang, Xiaoqin; Liu, Feng; Wang, Jing-Ru; Ding, Xiao-Lu; Yang, Yun; Zhang, Ruo-Nan; Zhao, Yuanyuan; Bi, Hai-Xia; Guo, Linxin; Gan, Wen-Juan; Wu, Hua

doi:10.1038/s41388-021-02160-2

Cited by 16 publications

(14 citation statements)

References 44 publications

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“…8A-B). We found an up-regulated BEST4 level which could contribute to the activation of AKT and ERK1/2, consistent with He et al study [30]. DGKB was previously found to be one of the gene signatures of prognostic prediction in CRC [29].…”

Section: Discussionsupporting

confidence: 92%

“…Among the 21 differentially expressed genes in the tumor section, two ZEA-promoted genes (bestrophin 4, BEST4; diacylglycerol kinase beta, DGKB) in the ZEA group were reported to be related to the malignant growth of colon cancer. BEST4 was found to be upregulated in CRC patients, and its high expression was correlated with a more advanced TNM stage, lymph node metastasis and worse survival rate by activating the BEST4/PI3K/AKT signaling pathway [30].…”

Section: Discussionmentioning

confidence: 98%

“…Moreover, among the identified serum metabolites, hippuric acid was significantly positively correlated with BEST4, JAK3, ROBO3 and CYP4F29P genes. In particular, BEST4, JAK3 and ROBO3 were reported to promote tumor cell proliferation through activating different signaling pathways, including the PI3K/AKT, JAK3/STAT3 and SLIT/ROBO pathways, respectively [30, 57, 58]. These results suggested that hippuric acid played a role in promoting tumor growth upon ZEA treatment through alteration of oncogenic gene expression.…”

Section: Discussionmentioning

confidence: 99%

“…was observed in the DGKB gene (Table 1), which was previously reported as one of the gene signatures in the prognostic prediction of CRC [29]. In addition, another up-regulated gene worth mentioning is BEST4, which was previously described to be overexpressed in CRC patients [30]. We then performed an enrichment analysis for KEGG pathways and MSigDB gene sets, including (1) cancer hallmarks, (2) oncogenic signatures and (3) chemical and genetic perturbations.…”

Section: Changes In Gene Expression Associated With Zea-induced Tumor...mentioning

confidence: 99%

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Mechanistic insights into zearalenone-accelerated colorectal cancer in mice using integrative multi-omics approaches

Wang

Lee

et al. 2022

Preprint

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Zearalenone (ZEA), a secondary metabolite from Fusarium fungi found in cereal-based foods, promotes the growth of colon, breast, and prostate cancers in vitro. However, the lack of animal studies hinders a deeper mechanistic understanding of the cancer promotive effect of ZEA. The aim of this study was to unveil the effect of ZEA on colon cancer progression and its underlying mechanism. Through integrative analyses of transcriptomics, metabolomics, metagenomics, and host phenotypes, we investigated the impact of a 4-week ZEA intervention on colorectal cancer in xenograft mice. Our results showed that a 4-week ZEA intervention increased the tumor weight twofold. ZEA exposure significantly increased the mRNA and protein levels of BEST4, DGKB and KI67, and the phosphorylation levels of ERK1/2 and AKT. Metabolomics analysis of the serum revealed the levels of amino acids, including histidine, arginine, citrulline and glycine decreased significantly in the ZEA group. Furthermore, ZEA lowered the alpha diversity of the gut microbiota and reduced the abundance of 9 genera, such as Tuzzerella and Rikenella, etc. Further association analysis indicated that Tuzzerella was negatively associated with the expression of BEST4 and DGKB genes, serum uric acid level and tumor weight. In addition, circulatory hippuric acid level was positively correlated with the tumor weight and the expression of oncogenic genes, including ROBO3, JAK3 and BEST4. Altogether, our results indicated that ZEA promoted colon cancer tumor progression through enhancing the BEST4/AKT/ERK1/2 pathway, lowering the circulatory amino acid concentration, alternating the gut microbiota composition, and suppressing the SCFA production.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Changes In Gene Expression Associated With Zea-induced Tumor...mentioning

confidence: 99%

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Mechanistic insights into zearalenone-accelerated colorectal cancer in mice using integrative multi-omics approaches

Wang

Lee

et al. 2022

Preprint

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“…BEST4 belongs to the bestrophin protein family that is widely expressed in human intestinal epithelial cells. Recent studies reported the oncogenic potential of BEST4 in colorectal carcinogenesis and metastasis by modulating PI3K/Akt signaling [ 38 , 39 ]. Although BEST4 was upregulated in ccRCC tissues compared with normal kidney tissues, based on the TCGA database, a good correlation with VSX1 was not observed in the GEO dataset.…”

Section: Discussionmentioning

confidence: 99%

High VSX1 expression promotes the aggressiveness of clear cell renal cell carcinoma by transcriptionally regulating FKBP10

Yang

et al. 2022

J Transl Med

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Background Clear cell renal cell carcinoma (ccRCC), the most common urological malignancy, has an unfavorable prognosis and an unknown mechanism of progression. Through survival analyses screening of The Cancer Genome Atlas (TCGA) dataset, we identified Visual system homeobox1 (VSX1) as a novel potential prognostic biomarker in ccRCC and subsequently investigated the oncogenic role of VSX1 in ccRCC. Methods The differential expression of VSX1 in human tumors and the clinical prognoses were analyzed in the TCGA dataset and Gene Expression Omnibus. Spearman’s correlation coefficient was determined for the correlation analysis of VSX1 expression and other genes of interest. The roles of VSX1 in cell proliferation, invasion, and migration of ccRCC cells were evaluated via the CCK-8 assay, colony formation assay, and Transwell assay, respectively. Further results were demonstrated by western blotting, immunohistochemistry, qRT-PCR, tumor sphere formation, flow cytometry, and the dual‑luciferase reporter assay. Results VSX1 mRNA upregulation was generally observed in multiple human malignancies from the TCGA database and was confirmed in ccRCC clinical specimens from our department. High VSX1 expression usually indicated that overall and disease-free survival were unfavorable for patients with ccRCC. In terms of mechanism, knockdown or overexpression of VSX1 affected ccRCC aggressiveness in vitro. The dual-luciferase reporter gene assay implied that VSX1 overexpression significantly increased the luciferase activity of TMEM44, FKBP10, and TRIB3, which indicated that VSX1 promoted ccRCC invasiveness via transcriptional regulation of these genes. The significantly enhanced growth in vitro that was induced by stable VSX1 overexpression was almost restored to normal by the knockdown of FKBP10. Conclusions This study demonstrated that VSX1 was a novel prognostic biomarker in ccRCC and that high VSX1 expression promoted cell proliferation, invasion, and migration in ccRCC via transcriptional activation of downstream target genes.

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Oncogenic potential of BEST4 in colorectal cancer via activation of PI3K/Akt signaling

Cited by 16 publications

References 44 publications

Mechanistic insights into zearalenone-accelerated colorectal cancer in mice using integrative multi-omics approaches

Mechanistic insights into zearalenone-accelerated colorectal cancer in mice using integrative multi-omics approaches

High VSX1 expression promotes the aggressiveness of clear cell renal cell carcinoma by transcriptionally regulating FKBP10

Single-cell resolution of the adult zebrafish intestine under conventional conditions and in response to an acute Vibrio cholerae infection

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