Bladder cancer (BC) is a heterogeneous disease entity exhibiting divergent phenotype, biological behavior and clinical outcome. About 70% of BC present as low-grade, superficial papillary tumors that are frequently recurrent but infrequently progress to high-grade muscle-invasive stages. The rest (~30%) of BC are high-grade and invasive at presentation, and they usually do have a prior history of low-grade, papillary tumors but are believed to arise de novo or derive from flat, high-grade carcinoma in situ lesions. Whether these two major phenotypic variants of BC are caused by distinct molecular alterations is of central importance in understanding and effectively managing BC. However, answer to this question remains elusive due to the lack of concerted research efforts. Over the past 15 years, we have been dissecting the molecular mechanisms of BC pathways by developing and analyzing genetically engineered mice via urothelium-specific gene activation or ablation or both. The resulting mouse models not only recapitulate many salient features of human BC, but yield new information regarding the cause-effect relationship between genes and pathways. The present proposal is designed to gain much deeper and broader insights into the combinatorial molecular events that together serve as the "drivers" to trigger BC formation along the two major phenotypic pathways.
Aim 1 will define the molecular alterations that are capable of synergizing with mutated fibroblast growth factor receptor 3 (FGFR3) to initiate low-grade, superficial papillary BC.
This Aim will focus on (i) the deficiency of pi 51 NK4b, p16lNK4a and p19ARF, three tumor suppressors located on 9p21 and frequently deleted in early-stage human BC;and (ii) the increased signaling of mutated FGFR3 through FGF signaling.
Aim 2 will examine the effects of gain-of-function p53 mutations and those in collaboration with pRb family deficiency in triggering high-grade invasive BC. A combination of cell culture, genetically engineered models and human studies will be used to accomplish the objectives. Collectively, these studies should help define the "molecular drivers" that are responsible for urothelial tumorigenesis along divergent pathways and help devise new biomarker panels for improved diagnosis, prognosis prediction and novel therapies of BC.

Public Health Relevance

Normal bladder epithelial cells can be converted into two major forms of tumors, one that often recurs thus requiring multiple therapies but infrequently invades, and another that does not recur but is often lethal. Elucidating the molecular mechanisms underlying each type of bladder tumors will open doors to tumor-type- specific approaches for diagnosis, prevention and therapy.

National Institute of Health (NIH)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
New York University
New York
United States
Zip Code
Zhang, Jingjie; Gao, Guangxun; Chen, Liang et al. (2014) Hydrogen peroxide/ATR-Chk2 activation mediates p53 protein stabilization and anti-cancer activity of cheliensisin A in human cancer cells. Oncotarget 5:841-52
Cao, Zipeng; Li, Xueyong; Li, Jingxia et al. (2014) X-linked inhibitor of apoptosis protein (XIAP) lacking RING domain localizes to the nuclear and promotes cancer cell anchorage-independent growth by targeting the E2F1/Cyclin E axis. Oncotarget 5:7126-37
Vieira, Neide; Deng, Fang-Ming; Liang, Feng-Xia et al. (2014) SNX31: a novel sorting nexin associated with the uroplakin-degrading multivesicular bodies in terminally differentiated urothelial cells. PLoS One 9:e99644
Zhang, Ruowen; Wang, Yulei; Li, Jingxia et al. (2014) The Chinese herb isolate yuanhuacine (YHL-14) induces G2/M arrest in human cancer cells by up-regulating p21 protein expression through an p53 protein-independent cascade. J Biol Chem 289:6394-403
Fang, Yong; Wang, Yihong; Wang, Yulei et al. (2014) A new tumour suppression mechanism by p27Kip1: EGFR down-regulation mediated by JNK/c-Jun pathway inhibition. Biochem J 463:383-92
Zhu, Junlan; Zhang, Jingjie; Huang, Haishan et al. (2014) Crucial role of c-Jun phosphorylation at Ser63/73 mediated by PHLPP protein degradation in the cheliensisin a inhibition of cell transformation. Cancer Prev Res (Phila) 7:1270-81
Madka, Venkateshwar; Mohammed, Altaf; Li, Qian et al. (2014) Chemoprevention of urothelial cell carcinoma growth and invasion by the dual COX-LOX inhibitor licofelone in UPII-SV40T transgenic mice. Cancer Prev Res (Phila) 7:708-16
Cao, Zipeng; Li, Xueyong; Li, Jingxia et al. (2014) SUMOylation of RhoGDI* is required for its repression of cyclin D1 expression and anchorage-independent growth of cancer cells. Mol Oncol 8:285-96
Huang, Haishan; Ma, Li; Li, Jingxia et al. (2014) NF-?B1 inhibits c-Myc protein degradation through suppression of FBW7 expression. Oncotarget 5:493-505
Gao, Guangxun; Chen, Liang; Li, Jingxia et al. (2014) Isorhapontigenin (ISO) inhibited cell transformation by inducing G0/G1 phase arrest via increasing MKP-1 mRNA Stability. Oncotarget 5:2664-77

Showing the most recent 10 out of 13 publications