Dopamine receptor D2 genetic variations is associated with the risk and clinicopathological variables of urothelial cell carcinoma in a Taiwanese population

Tung, Min‐Che; Wen, Yu; Wang, Shian Shiang; Lin, Yung Wei; Liu, Yucheng; Yang, Shun Fa; Chien, Ming Hsien

doi:10.7150/ijms.26895

Cited by 8 publications

(6 citation statements)

References 34 publications

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“…haloperidol) have a reduced cancer risk in different solid tumors, including those of the rectum, colon, and prostate, suggesting that dopaminergic signaling pathways may be associated with the carcinogenesis of cancer [ 14 , 32 – 34 ]. Multiple researchers have shown increased expression of dopamine receptors in malignancies [ 14 , 17 , 35 ]. Meredith et.…”

Section: Discussionmentioning

confidence: 99%

Targeting dopamine receptor D2 as a novel therapeutic strategy in endometrial cancer

Pierce

Fang

Yin

et al. 2021

J Exp Clin Cancer Res

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Background ONC201 is a dopamine receptor D2 (DRD2) antagonist that inhibits tumor growth in preclinical models through ClpP activation to induce integrated stress response pathway and mitochondrial events related to inhibition of cell growth, which is being explored in clinical trials for solid tumors and hematological malignancies. In this study, we investigated the anti-tumorigenic effect of ONC201 in endometrial cancer cell lines and a genetically engineered mouse model of endometrial cancer. Methods Cell proliferation was assessed by MTT and colony formation assays. Cell cycle and apoptosis were evaluated by Cellometer. Invasion capacity was tested using adhesion, transwell and wound healing assays. LKB1fl/flp53fl/fl mouse model of endometrial cancer were fed a control low fat diet versus a high fat diet to mimic diet-induced obesity. Following tumor onset, mice were treated with placebo or ONC201. Metabolomics and lipidomics were used to identify the obesity-dependent effects of ONC201 in the mouse endometrial tumors. DRD2 expression was analyzed by immunohistochemistry in human endometrioid and serous carcinoma specimens. DRD2 mRNA expression from the Cancer Genome Atlas (TCGA) database was compared between the four molecular subtypes of endometrial cancer. Results Increasing DRD2 expression in endometrial cancer was significantly associated with grade, serous histology and stage, as well as worse progression free survival and overall survival. Higher expression of DRD2 mRNA was found for the Copy Number High (CNH) subtype when compared to the other subtypes. ONC201 inhibited cell proliferation, induced cell cycle G1 arrest, caused cellular stress and apoptosis and reduced invasion in endometrial cancer cells. Diet-induced obesity promoted endometrial tumor growth while ONC201 exhibited anti-tumorigenic efficacy in the obese and lean LKB1fl/fl/p53fl/fl mice. Metabolomic analysis demonstrated that ONC201 reversed the obesity-driven upregulation of lipid biosynthesis and reduced protein biosynthesis in obese and lean mice. Conclusion ONC201 has anti-tumorigenic effects in endometrial cancer cells and a transgenic mouse model of endometrial cancer, and DRD2 expression was documented in both human serous and endometrioid endometrial cancer. These studies support DRD2 antagonism via ONC201 as a promising therapeutic strategy for endometrial cancer that has already demonstrated pharmacodynamic activity and clinical benefit in both serous and endometrioid endometrial cancer patients.

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Section: Discussionmentioning

confidence: 99%

Targeting dopamine receptor D2 as a novel therapeutic strategy in endometrial cancer

Pierce

Fang

Yin

et al. 2021

J Exp Clin Cancer Res

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“…GAS5 expression, classified into low expression (<median) and high expression (>median), were generated with respect to overall survival using the Kaplan-Meier method. Then p-values were calculated using a log-rank test [18].…”

Section: Gas5 Expression Analysis Of the Cancer Genome Atlasmentioning

confidence: 99%

Impact of Gene Polymorphisms in GAS5 on Urothelial Cell Carcinoma Development and Clinical Characteristics

Weng

Chen

et al. 2020

Diagnostics

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Urothelial cell carcinoma (UCC) is the commonest malignant tumor of the urinary tract and the second most common kidney cancer malignancy. Growth arrest-specific 5 (GAS5), a long noncoding RNA, is encoded by the GAS5 gene and plays a critical role in cellular growth arrest and apoptosis. In the current study, two single nucleotide polymorphisms (SNPs) in the GAS5 gene, rs145204276 and rs55829688, were selected to investigate correlations between these single SNPs and susceptibility to UCC. A total of 430 UCC cases and 860 ethnically matched healthy controls were included. SNP rs145204276 and SNP rs55829688 were determined using a TaqMan genotyping assay. Logistic regression models demonstrated that female patients with UCC carrying the rs145204276 GAS5 Ins/Del or Del/Del genotype had a 3.037-fold higher risk of larger tumor status (95% confidence interval 1.259–7.324) than did rs145204276 wild type (Ins/Ins) carriers (p = 0.011). The Cancer Genome Atlas validation cohort analysis demonstrated that the expression of GAS5 in female patients with bladder urothelial carcinoma (BLCA) with larger tumor size was much lower than that in patients with a smaller tumor size (p = 0.041). Kaplan-Meier curve analysis and the log–rank test revealed that female patients with BLCA and lower GAS5 expression had poorer overall survival than those with higher GAS5 expression. In conclusion, genetic variations in GAS5 rs145204276 may serve as a critical predictor of the clinical status of female patients with UCC.

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“…Ang2 acts as an autocrine factor in supporting endothelial cell homeostasis and counteracts Ang1 to sensitize endothelium 6. Genetic factors and single nucleotide polymorphisms (SNPs) genotyping are both pivotal to explore the risk and prognosis of tumorigenesis 7-9. SNPs in the Ang2 intron are known to be associated with breast cancer, lung injury, or acute respiratory distress syndrome 10-12.…”

Section: Introductionmentioning

confidence: 99%

Correlations between angiopoietin-2 gene polymorphisms and lung cancer progression in a Chinese Han population

Tang¹,

Chen²,

Jin³

et al. 2019

J. Cancer

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Lung cancer is the most common malignancy in China and is associated with a poor survival rate amongst Han Chinese. The high mortality is largely attributed to late-stage diagnosis, when treatment is largely ineffective. Identification of genetic variants could potentially assist with earlier diagnosis and thus more effective treatment. The development and progression of lung cancer is stimulated by angiopoietin-2 (Ang2), a ligand for Tie2, an endothelial tyrosine kinase. Patients with lung cancer with higher serum Ang2 levels have significantly poorer survival than patients with lower serum Ang2 levels. We explored the effects of Ang2 single nucleotide polymorphisms (SNPs) on lung cancer susceptibility. We used lung cancer tissue and serum samples to measure Ang2 expression in a Chinese Han population. Five Ang2 SNPs (rs2442598, rs734701, rs1823375, 11137037, and rs12674822) were analyzed using TaqMan SNP genotyping in 695 patients with lung cancer and 900 cancer-free controls. Carriers of the variant GT allele of rs12674822 had a higher risk of lung cancer than wild-type (GG) carriers, while the presence of the CC genotype at rs11137037 was associated with higher clinical stage disease compared with having the AA genotype. Our study is the first to document a correlation between Ang2 polymorphisms and lung cancer development and progression in people of Chinese Han ethnicity.

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Dopamine receptor D2 genetic variations is associated with the risk and clinicopathological variables of urothelial cell carcinoma in a Taiwanese population

Cited by 8 publications

References 34 publications

Targeting dopamine receptor D2 as a novel therapeutic strategy in endometrial cancer

Targeting dopamine receptor D2 as a novel therapeutic strategy in endometrial cancer

Impact of Gene Polymorphisms in GAS5 on Urothelial Cell Carcinoma Development and Clinical Characteristics

Correlations between angiopoietin-2 gene polymorphisms and lung cancer progression in a Chinese Han population

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