Project 2. Cross regulation of TGFB/elf, B-catenin and vitamin D pathways in gastrointestinal cancers. Human hepatocellular carcinoma and gastric cancer are characterized by alterations in the cadherin/catenin adhesion and signaling system. In some situations this is a result of activating mutations in P-catenin and in others, inactivation or mutation of the E-cadherin gene. The alterations in cell signaling and cell adhesion that accompany these genetic changes likely contribute to the oncogenic potential of these and other foregut cancers. Defects in TGFB/smad signaling are also common in cancers of the liver and intestinal tract. In addition to its """"""""canonical"""""""" effects the TGFB/smad pathway can also interact with the B-catenin/TCF transcriptional machinery and co-operatively regulate transcription of a number of genes. The phenotype of the elf[+/-] and elf[+/-]/smacd4[-/-]mice, in which altered TGFB signaling is accompanied by changes in E-cadherin and B-catenin links these two pathways for the first time in a human disease and provides important clues regarding a potential common basis for the development of human foregut cancers. In our first aim we will use transgenic animal models, cell lines and explants to investigate the role of B-catenin signaling in hepatocellular, gastric and pancreatic cancers and determine the molecular basis of its cross-regulation by TGFB/smad signaling. We will specifically ask if activation of wnt/catenin signaling and the wnt/catenin regulated gene FGFBP is required for the tumorigenic phenotype of the elf[+/-] and elf[+/-]/smad4[-/-] and elf[+/-] /smad3[+/-] mice.
In aim 2 we will test the hypothesis that the vitamin D pathway provides a potential preventive and therapeutic option for the treatment of HCC and GC. Preliminary data demonstrates that the wnt/B-catenin/TCF pathway is a key intermediary in the cancer preventive action of vitamin D and its analogues. Vitamin D represses B-catenin signaling and B-catenin activates VDR. Both smads and B-catenin can bind directly to the vitamin D receptor (VDR) and potentiate its transactivation activity. Vitamin D and its analogues are potent repressers of the growth of several different tumor types including hepatocellular and gastric cancer and vitamin D is already in early clinical trials for the treatment of hepatocellular cancer.
In aim 2 we will test the activity of vitamin D and of newly developed """"""""B-catenin specific"""""""" vitamin D analogues in the animal models described above and use VDR knockdown in vitro and VDR transgenic animals to examine to role of the vitamin D receptor. A therapeutic strategy involving ligand-mediated activation of the VDR offers the potential benefit of repressing B-catenin signaling and activating the TGFB pathway at the same time as VDR is activated. These data will be linked to the expression of activated B-catenin and markers of altered TGFB/smad signaling in 120 frozen hepatocellular carcinomas and paired control tissues. This collection, annotated with pathological, clinical and outcome data will provide an unprecedented opportunity to compare our transgenic animal data directly with human material.
|Korkut, Anil; Zaidi, Sobia; Kanchi, Rupa S et al. (2018) A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-? Superfamily. Cell Syst 7:422-437.e7|
|Chen, Jian; Zaidi, Sobia; Rao, Shuyun et al. (2018) Analysis of Genomes and Transcriptomes of Hepatocellular Carcinomas Identifies Mutations and Gene Expression Changes in the Transforming Growth Factor-? Pathway. Gastroenterology 154:195-210|
|Lin, Shu-Hong; Raju, Gottumukkala S; Huff, Chad et al. (2018) The somatic mutation landscape of premalignant colorectal adenoma. Gut 67:1299-1305|
|Rao, Shuyun; Zaidi, Sobia; Banerjee, Jaideep et al. (2017) Transforming growth factor-? in liver cancer stem cells and regeneration. Hepatol Commun 1:477-493|
|Zhou, Xin; Patel, Darshan; Sen, Sabyasachi et al. (2017) Poly-ADP-ribose polymerase inhibition enhances ischemic and diabetic wound healing by promoting angiogenesis. J Vasc Surg 65:1161-1169|
|Gu, Shoujun; Nguyen, Bao-Ngoc; Rao, Shuyun et al. (2017) Alcohol, stem cells and cancer. Genes Cancer 8:695-700|
|Chen, Jian; Shukla, Vivek; Farci, Patrizia et al. (2017) Loss of the transforming growth factor-? effector ?2-Spectrin promotes genomic instability. Hepatology 65:678-693|
|Shin, Joshua; Mishra, Viveka; Glasgow, Eric et al. (2017) PRAJA is overexpressed in glioblastoma and contributes to neural precursor development. Genes Cancer 8:640-649|
|Long, Yin; Sanchez-Espiridion, Beatriz; Lin, Moubin et al. (2017) Global and targeted serum metabolic profiling of colorectal cancer progression. Cancer 123:4066-4074|
|Mitra, Abhisek; Yan, Jun; Xia, Xueqing et al. (2017) IL6-mediated inflammatory loop reprograms normal to epithelial-mesenchymal transition+ metastatic cancer stem cells in preneoplastic liver of transforming growth factor beta-deficient ?2-spectrin+/- mice. Hepatology 65:1222-1236|
Showing the most recent 10 out of 139 publications