Hepatocellular carcinoma (HCC) is the most common malignant tumor of the liver and the third leading cause of death from cancer. However, currently there is no effective treatment for HCC. It is therefore urgent to develop novel therapeutic approaches for the treatment of HCC. Increasing evidence suggests that being able to modulate specific miRNAs may lead to the development of novel cancer therapies. Our studies (and others) indicate that a microRNA, miR-26a, represses proinflammatory cytokines, especially interleukin 6 (IL-6) and its downstream mediator, signal transducer and activator of transcription 3 (STAT3), suggesting a tumor suppressive role of miR-26a on HCC development. However, the role of miR-26a in HCC development in the setting consisting of both hepatocytes and Kupffer cells in appropriate HCC mouse models has not been determined. Furthermore, whether modulating miR-26a in hepatocytes and/or Kupffer cells can be an effective therapeutic approach for treating HCC has not been tested. The objective of this proposal is to investigate the molecular and cellular mechanisms by which miR-26a overexpression in hepatocytes and Kupffer cells inhibits HCC development. In addition, we have identified small molecules and developed siRNA/RNA in vivo targeted delivery technology that can increase miR-26a expression in the liver.
In Aim 1, we will determine the effect of overexpression of miR-26a in hepatocytes and in Kupffer cells on suppression of HCC development. We have generated hepatocyte-specific as well as Kupffer cell-specific miR-26a overexpression transgenic mice. We will use these unique transgenic mouse lines to define the cellular and molecular mechanisms by which miR-26a exerts its effect on HCC.
In Aim 2, we will determine the effect of small molecules on miR-26a induction and HCC suppression. We have also developed an innovative siRNA/RNA in vivo targeted delivery technology-- CpG-siRNA/RNA?that enables RNA in vivo delivery into Toll-like Receptor 9-positive Kupffer cells and inflammatory/malignant hepatocytes. CpG-Stat3 siRNA is moving towards clinical trials for glioma and lymphoma patients at City of Hope. We will assess the effect of both CpG-miR-26a and CpG-Stat3 siRNA on HCC development in hepatocytes or/and Kupffer cells in animal models. The proposed studies will not only provide mechanistic insights into pathways underlying HCC but also help to develop effective treatment strategies for HCC.

Public Health Relevance

We propose to extend our previous research to investigate the cellular and molecular mechanism by which a micro-RNA modulates the development of liver cancer. We will also determine the effect of small molecules and a novel targeted delivery technology to inhibit liver cancer development through inducing the expression of micro-RNA in the liver. The results may lay the foundation to develop new and effective treatment for liver cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Drug Discovery and Molecular Pharmacology Study Section (DMP)
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Alley, Michael C
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Beckman Research Institute/City of Hope
United States
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Li, Shishi; Pan, Huaye; Tan, Chao et al. (2018) Mitochondrial Dysfunctions Contribute to Hypertrophic Cardiomyopathy in Patient iPSC-Derived Cardiomyocytes with MT-RNR2 Mutation. Stem Cell Reports 10:808-821
Gu, Ying; Zhang, Jiawei; Ma, Xiaoxiao et al. (2017) Stabilization of the c-Myc Protein by CAMKII? Promotes T Cell Lymphoma. Cancer Cell 32:115-128.e7
Wang, Yangmeng; Paulo, Esther; Wu, Dongmei et al. (2017) Adipocyte Liver Kinase b1 Suppresses Beige Adipocyte Renaissance Through Class IIa Histone Deacetylase 4. Diabetes 66:2952-2963
Meng, Z; Ma, X; Du, J et al. (2017) CAMK2? antagonizes mTORC1 activation during hepatocarcinogenesis. Oncogene 36:2446-2456
Su, Jia; Zhang, Qiqi; Qi, Hui et al. (2017) The G-protein-coupled bile acid receptor Gpbar1 (TGR5) protects against renal inflammation and renal cancer cell proliferation and migration through antagonizing NF-?B and STAT3 signaling pathways. Oncotarget 8:54378-54387
Ma, X; Meng, Z; Jin, L et al. (2017) CAMK2? in intestinal epithelial cells modulates colitis-associated colorectal carcinogenesis via enhancing STAT3 activation. Oncogene 36:4060-4071
Tian, Jingyan; Huang, Silvia; Sun, Siming et al. (2017) Bile acid signaling and bariatric surgery. Liver Res 1:208-213
Ding, Lili; Sousa, Kyle M; Jin, Lihua et al. (2016) Vertical sleeve gastrectomy activates GPBAR-1/TGR5 to sustain weight loss, improve fatty liver, and remit insulin resistance in mice. Hepatology 64:760-73
Gu, Y; Zheng, W; Zhang, J et al. (2016) Aberrant activation of CaMKII? accelerates chronic myeloid leukemia blast crisis. Leukemia 30:1282-9
Xia, Brian; Gerstin, Ed; Schones, Dustin E et al. (2016) Transgenerational programming of longevity through E(z)-mediated histone H3K27 trimethylation in Drosophila. Aging (Albany NY) 8:2988-3008

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