Liver cancers are highly malignant neoplasms with poor prognosis. The tumors usually develop in the presence of continuous inflammation and epithelial regeneration in the setting of chronic hepatobiliary diseases. The pathogenesis of liver carcinogenesis is complex and involves alterations of multiple genes by mutations, epigenetic regulation, noncoding RNAs and translational modifications of encoded proteins. Transforming growth factor (TGF)- signaling pathway is pivotal in liver carcinogenesis. Studies from our lab supported by the previous project have shown that the prostaglandin (PG) signaling pathway is active during hepatic carcinogenesis and that the PG cascade subverts TGF--mediated mitoinhibition in liver cancer cells. These findings support the hypothesis that loss of responsiveness to the antiproliferative actions of TGF- is a prerequisite for liver cancer development and that subversion of TGF--mediated mitoinhibition by PG pathway is critical in hepatic carcinogenesis. In the current continuation application, we will further investigate the molecular mechanism and function of TGF- and related signaling pathways in liver carcinogenesis. On the basis of our published studies and new preliminary data, we hypothesize that the long non-coding RNA, MALAT1, is a novel negative regulator of R- Smad which terminates TGF- signaling and thus promotes liver carcinogenesis. We further postulate that 15-keto-PGE2, a metabolite of PGE2 catalyzed by 15-PGDH, is a novel endogenous ligand for PPAR-? which enhances TGF-/R-Smad signaling and thus inhibits liver carcinogenesis. These hypotheses will be examined in three specific aims using complementary in vitro biochemical and molecular analyses and in vivo animal models.
In Aim 1, we will investigate the hypothesis that MALAT1 associates with PPM1A (R-Smad C-terminus phosphatase) and recruits Smad2/3 through SETD2, forming a lncRNA-protein complex that terminate TGF-/R-Smad signaling.
Aim 2 is designed to examine the hypothesis that 15-PGDH-derived 15-keto-PGE2 is an endogenous PPAR-? ligand that activates Smad2/3 pathway and inhibits liver cancer development.
Aim 3 will evaluate the interplay between MALAT1 and 15-PGDH signaling cascades for Smad2/3 activation in tumor-initiating hepatocytes. The proposed studies will further define the molecular mechanisms of hepatic carcinogenesis and provide important implication for development of new target therapies.

Public Health Relevance

Liver cancers are highly malignant neoplasms with poor prognosis. As the tumors are resistant to commonly used chemotherapy and radiotherapy, it is imperative to develop new strategies for more effective therapy. This proposal is highly significant as it will identify key mechanisms of liver carcinogenesis and explore new therapeutic options.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
High Priority, Short Term Project Award (R56)
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Molecular Oncogenesis Study Section (MONC)
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Sherker, Averell H
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Tulane University
Internal Medicine/Medicine
Schools of Medicine
New Orleans
United States
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Ungerleider, Nathan; Han, Chang; Zhang, Jinqiang et al. (2017) TGF? signaling confers sorafenib resistance via induction of multiple RTKs in hepatocellular carcinoma cells. Mol Carcinog 56:1302-1311
Song, Kyoungsub; Kwon, Hyunjoo; Han, Chang et al. (2015) Active glycolytic metabolism in CD133(+) hepatocellular cancer stem cells: regulation by MIR-122. Oncotarget 6:40822-35
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Chen, Weina; Han, Chang; Zhang, Jinqiang et al. (2015) miR-150 Deficiency Protects against FAS-Induced Acute Liver Injury in Mice through Regulation of AKT. PLoS One 10:e0132734
Zhu, Hanqing; Han, Chang; Lu, Dongdong et al. (2014) miR-17-92 cluster promotes cholangiocarcinoma growth: evidence for PTEN as downstream target and IL-6/Stat3 as upstream activator. Am J Pathol 184:2828-39
Lu, Lu; Byrnes, Kathleen; Han, Chang et al. (2014) miR-21 targets 15-PGDH and promotes cholangiocarcinoma growth. Mol Cancer Res 12:890-900
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Lu, D; Han, C; Wu, T (2014) 15-PGDH inhibits hepatocellular carcinoma growth through 15-keto-PGE2/PPAR?-mediated activation of p21WAF1/Cip1. Oncogene 33:1101-12
Lu, Dongdong; Han, Chang; Wu, Tong (2013) 15-hydroxyprostaglandin dehydrogenase-derived 15-keto-prostaglandin E2 inhibits cholangiocarcinoma cell growth through interaction with peroxisome proliferator-activated receptor-?, SMAD2/3, and TAP63 proteins. J Biol Chem 288:19484-502
Wang, Ying; Han, Chang; Lu, Lu et al. (2013) Hedgehog signaling pathway regulates autophagy in human hepatocellular carcinoma cells. Hepatology 58:995-1010

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