Bladder cancer (BC) is the fifth most frequent cancer found in the United States (US). Tobacco smoke (TS) is the major cause of BC in US, and tobacco smokers have a 5-fold higher BC incidence than nonsmokers. TS contains more than 60 carcinogens;however, which carcinogens are responsible for BC is not well established. Arylamines, 4-hydroxy-aminoblphenyl (ABP) in particular, are the major cause of occupation-related BC, but the amount of arylamines in TS is minute. In fact, TS contains 100,000 fold more acrolein (Acr) than ABP, and Acr is a potent and organ-specific carcinogen capable of Inducing BC in rat models. Our laboratory has a longstanding interest in studying the role of chemical carcinogen induced DNA damage and repair in tumorigenesis. We recently made three important findings regarding Acr: (1) Acr damages DNA by forming Acr-DNA adducts that are mutagenic;(ii) Acr inhibits DNA repair by modifying and accelerating autophagy-mediated degradation of the modified DNA repair proteins;and (iii) Acr-DNA adducts are poorly repaired in human cells. We propose that Acr Is a major bladder carcinogen and its carcinogenicity Is via these three detrimental effects (Hypothesis 1). Most BC can be classified as either noninvasive (N-lnv) or invasive (Inv);while N-lnv-BC often bear mutations in codon 12 ofthe H-RAS (<20%) and codons 248, 249, 372 and 652 ofthe FGFRS gene (80%), Inv-BC mainly carry mutations in the p53 (30-60%) and RB genes. We hypothesize that these mutation hotspots in BC are Acr preferential binding sites in bladder urothelial cells (Hypothesis 2). We found that DNA damage induces much higher mutations in Inv-BC cells than in N-lnv-BC cells and that N-lnv-BC cells have a much higher DNA damage repair capacity than Inv-BC cells. We also recently found that p63 gene is highly expressed in N-lnv-BC but not in Inv-BC cells, and that introduction of p63 gene elevates DNA repair capacity in Inv-BC cells. These results lead us to hypothesize that H- RAS/FGFR3 mutation-activation enhances DNA repair capacity via activation of p63 and that p53 mutations reduce DNA repair capacity via down regulation of p63 (Hypothesis 3). We will test these hypotheses in cultured human urothelial cells, human bladder tumor tissue samples and transgenic mouse models to understand the relationship between DNA repair capacity and divergent pathways of bladder cancer.

Public Health Relevance

Tobacco smoke (TS) is believed to be the cause of half of all bladder cancer, but the exact cancer-causing carcinogen in TS remains elusive. Our studies will help define the type of carcinogen and how it causes different levels of DNA damage in different types of bladder cancer. Our results should provide novel insights into the pathogenesis of bladder cancer and how this prevalent disease can be better prevented.

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Jin, Honglei; Sun, Wenrui; Zhang, Yuanmei et al. (2018) MicroRNA-411 Downregulation Enhances Tumor Growth by Upregulating MLLT11 Expression in Human Bladder Cancer. Mol Ther Nucleic Acids 11:312-322
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Li, Xin; Tian, Zhongxian; Jin, Honglei et al. (2018) Decreased c-Myc mRNA Stability via the MicroRNA 141-3p/AUF1 Axis Is Crucial for p63? Inhibition of Cyclin D1 Gene Transcription and Bladder Cancer Cell Tumorigenicity. Mol Cell Biol 38:
Guo, Xirui; Huang, Haishan; Jin, Honglei et al. (2018) ISO, via Upregulating MiR-137 Transcription, Inhibits GSK3?-HSP70-MMP-2 Axis, Resulting in Attenuating Urothelial Cancer Invasion. Mol Ther Nucleic Acids 12:337-349
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Yu, Yonghui; Jin, Honglei; Xu, Jiheng et al. (2018) XIAP overexpression promotes bladder cancer invasion in vitro and lung metastasis in vivo via enhancing nucleolin-mediated Rho-GDI? mRNA stability. Int J Cancer 142:2040-2055
Lee, Hyun-Wook; Park, Sung-Hyun; Weng, Mao-Wen et al. (2018) E-cigarette smoke damages DNA and reduces repair activity in mouse lung, heart, and bladder as well as in human lung and bladder cells. Proc Natl Acad Sci U S A 115:E1560-E1569
Jin, Honglei; Xie, Qipeng; Guo, Xirui et al. (2017) p63? protein up-regulates heat shock protein 70 expression via E2F1 transcription factor 1, promoting Wasf3/Wave3/MMP9 signaling and bladder cancer invasion. J Biol Chem 292:15952-15963
Huang, Haishan; Jin, Honglei; Zhao, Huirong et al. (2017) RhoGDI? promotes Sp1/MMP-2 expression and bladder cancer invasion through perturbing miR-200c-targeted JNK2 protein translation. Mol Oncol 11:1579-1594

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