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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56DK077776-06A1
Application #
9131849
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Sherker, Averell H
Project Start
2007-04-01
Project End
2016-08-31
Budget Start
2015-09-01
Budget End
2016-08-31
Support Year
6
Fiscal Year
2015
Total Cost
$225,750
Indirect Cost
$75,750
Name
Tulane University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
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
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
Chen, Weina; Han, Chang; Zhang, Jinqiang et al. (2015) Deletion of Mir155 prevents Fas-induced liver injury through up-regulation of Mcl-1. Am J Pathol 185:1033-44
Lu, Lu; Byrnes, Kathleen; Han, Chang et al. (2014) miR-21 targets 15-PGDH and promotes cholangiocarcinoma growth. Mol Cancer Res 12:890-900
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
Qadir, Ximena V; Han, Chang; Lu, Dongdong et al. (2014) miR-185 inhibits hepatocellular carcinoma growth by targeting the DNMT1/PTEN/Akt pathway. Am J Pathol 184:2355-64
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-γ, 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
Zhang, Jinqiang; Han, Chang; Wu, Tong (2012) MicroRNA-26a promotes cholangiocarcinoma growth by activating β-catenin. Gastroenterology 143:246-56.e8
Lu, D; Han, C; Wu, T (2012) Microsomal prostaglandin E synthase-1 promotes hepatocarcinogenesis through activation of a novel EGR1/β-catenin signaling axis. Oncogene 31:842-57

Showing the most recent 10 out of 11 publications