Our study aimed to investigate potential drug development targets for bladder cancer through MR and co-localization analyses of 4907 proteins. The MR analysis identified 47 potential drug targets, while the co-localization analysis narrowed it down to 32 targets. Additionally, we validated 6 therapeutic targets in the Finnish database of BC.
Our findings showed that genes including GSTM1, GSTM3, and GSTM4 were associated with a reduced risk of bladder cancer. These genes belong to a family of proteins called glutathione sulfotransferases (GSTs), which play a crucial role in metabolizing carcinogens and converting toxic compounds into less harmful forms(Hayes and Pulford, 1995, Strange et al., 2001).Previous studies have shown that the GSTM1 null genotype is associated with an increased risk of various cancers, such as colorectal(Song et al., 2020), cervical, and ovarian cancer(Ye et al., 2022). This suggests that mutations in GST genes, known as polymorphisms, could impact the detoxifying function of these enzymes and increase cancer susceptibility.A meta-study (Zhou et al., 2018)by Zhou et al. also found that GSTM1 null and GSTT1 null genotypes are risk factors for bladder cancer susceptibility and are involved in the pathogenesis of the disease. Furthermore, smoking, which is a significant risk factor for bladder cancer(Xiong et al., 2022), has been associated with elevated levels of oxidative DNA and lipid damage byproducts(Tang et al., 2019). GSTM1 and GSTA1 enzymes, due to their antioxidant and detoxifying capabilities, may provide protection against such harm, particularly induced by smoking.Our investigation further highlighted the protective roles of GSTM3 and GSTM4 against bladder cancer development. GSTM3 is involved in detoxification and scavenging of reactive oxygen species (ROS) produced by tobacco. Mutations in intron 6 of GSTM3 have been found to increase susceptibility to bladder cancer(Singh et al., 2008). The binding of ROS to glutathione, catalyzed by GSTM3, may protect cells from electrophilic damage(Tan et al., 2013). On the other hand, GSTM4, another member of the GST family, has fewer studies investigating its role in bladder cancer, and further research is needed to explore its potential protective effects.Overall, our study identified potential therapeutic targets for bladder cancer, particularly within the GSTM family of proteins. These findings contribute to our understanding of the role of GSTs in bladder cancer development and suggest avenues for future drug development and research.
Our study showed DLK1 as a risk factor for bladder cancer.DLK1 is expressed in many human tissues during embryonic development, but is expressed at a lower level in adults and is mainly restricted to (neuro)endocrine tissues and other immature stem/progenitor cells. There is now a growing consensus that tumorigenesis is closely linked to the involvement of tissue development and homeostatic imbalances(Pittaway et al., 2021). While DLK1 is widely present in lung cancer as an abnormally expressed (Tan et al., 2019) and high-grade plasmacytoid ovarian cancer(Huang et al., 2019) and colorectal cancer (Li et al., 2022)etc., suggesting that DLK1 may play an important role in tumor progression and metastasis.Although substantial evidence from expression and functional data suggests a role for DLK1 in many malignancies, it is unclear what leads to the upregulation of DLK1 and its reversion to the stem phenotype in these cancers. In a glioma-derived study, stable transfection of DLK1 cDNA expression vectors into GBM cell lines resulted in enhanced proliferation. In addition, they lost contact inhibition and had significantly greater migratory capacity(Yin et al., 2006).Indeed, a growing body of evidence suggests that treatment resistance and recurrence are primarily due to the survival of cancer cells presenting a stemness phenotype, often enriched in specialized microenvironments, and that DLK1 can play a role in the regulation and maintenance of this phenotype (Pittaway et al., 2021). In summary in the future more studies are expected to explore DLK1 as a target for the treatment of bladder cancer.
Our study identified CSF2RB as a risk factor for bladder cancer, and colony-stimulating factor 2 receptor subunit β (CSF2RB; CD131) as a common subunit of the type I cytokine receptors for granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3, and IL-5 (Côrte-Real et al., 2022) .A study showed that low expression of CSF2RB was closely associated with late clinicopathologic stage and poor prognosis in patients with lung adenocarcinoma, making CSF2RB an independent prognostic factor(Hercus et al., 2018) .GM-CSF, IL3, CSF2 and IL5 are important regulators of inflammation and immunosuppression in the tumor microenvironment(Dougan et al., 2019). They can generate proliferative and survival signals for many malignancies, such as leukemia, small cell lung cancer, melanoma, breast and prostate cancer(Hong et al., 2020, Berraondo et al., 2019).In a leukemia study we found that CSF2RB knockdown reduced the proliferation of human AML cell lines expressing FLT3-ITD, resulting in reduced disease burden and improved survival. And the impaired oncogenic potential of FLT3-ITD after CSF2RB knockdown was associated with reduced STAT5 phosphorylation (Berraondo et al., 2019)and thus CSF2RB as a target for bladder cancer has a certain value of exploration in the future.
The CNDP1 gene encodes a 57 kDa M20 metallopeptidase family glycoprotein. In humans, it is expressed predominantly in the central nervous system and (to a lesser extent) secreted as a homodimer in the liver(Teufel et al., 2003). In a large number of prostate cancer patients with lymph node metastases, low levels of CNDP1 have been found to be associated with tumor metastasis (Schwenk et al., 2010).Another study showed that reduced CNDP1 levels were associated with malignant disease in patients with digestive tract tumors (Arner et al., 2015).Whereas our study concluded that CNDP1 is a risk factor for bladder cancer, these two studies seem to be contradictory to our conclusions, and considering the small sample sizes of these two studies, we look forward to more in the future to confirm our viewpoints. agouti signaling protein (ASIP) gene is a major determinant of hair and skin hyperpigmentation(Bonilla et al., 2005). The current study suggests that it is closely related to skin cancer and basal cell carcinoma(Gudbjartsson et al., 2008). However, the relationship between this gene and bladder cancer is unclear, and more research is needed to explore ASIP and skin cancer in the future.
The study has several limitations. Firstly, bladder cancer can be classified into various tissue types, including bladder uroepithelial carcinoma, bladder adenocarcinoma, and bladder sarcoma. However, there is currently a lack of GWAS datasets available for a broader range of bladder cancer subtypes. Secondly, our results only predict potential therapeutic targets for bladder cancer. Further validation through extensive clinical and epidemiological studies is needed to confirm our findings. Additionally, the pqtl database is relatively homogeneous, and the inclusion of more diverse pqtl databases is necessary to validate our findings in the future.
Our study contributes to understanding the relationship between circulating proteins and bladder cancer. By utilizing Mendelian randomization and co-localization analysis, we have identified seven proteins that are closely associated with bladder cancer. These findings form a crucial basis for future investigations aimed at discovering potential targets for bladder cancer treatment.