Hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide. Often the disease is diagnosed at a late stage of high-grade cancer progression that is resistant to the available therapies. HCC is also a significant problem among the Veterans. According to VA Research Currents (Mike Richman, 2017, VA website) the outlook for hepatocellular carcinoma among the US Veterans is bleak, as it is increasing at a rate about five times greater than that of general US population. A 2015 study indicated that HCC among US Veterans is going peak in the year of 2021. Clearly, a greater understanding of the molecular mechanisms underlying HCC will be important for development of efficacious therapeutic strategies. This proposal focuses on the fork-head box M1 (FoxM1) gene because it is essential for HCC development and progression. Also, overexpression of FoxM1 in HCC predicts poor prognosis. FoxM1 has been extensively studied as an activator of genes involved in proliferation, pluripotency, and metastasis. Recently, we discovered a repression function of FoxM1. In this proposal we will investigate the hypothesis is that the newly discovered repression function of FoxM1 plays critical roles in the development and progression of HCC. We are using a Ras-transgenic model for HCC, mainly because the Ras-pathway is ubiquitously activated in human HCC through epigenetic silencing of its regulators. Using that model, we showed that conditional deletion of FoxM1 after HCC development causes preferential loss of the liver cancer stem cells (LCSCs). Interestingly, we observed that FoxM1 represses the liver differentiation gene FoxA2. Repression of FoxA2 by FoxM1 involves interactions of FoxM1 with the Rb-family proteins, and it occurs in G1 phase of the cell cycle. We will investigate the hypothesis that G1 phase repression of FoxM1 is important for the mechanism by which FoxM1 supports the liver cancer stem cells. We have developed a novel knock-in mouse strain that expresses a mutant FoxM1 deficient in the repression function, but retains its ability to activate transcription. That strain will be used to investigate the significance of the repression function in liver cancer development and liver cancer stem cells. In addition, using that knock-in mouse strain, we will determine whether the repression function of FoxM1 is important for recovery from chronic liver injury.
The specific aims are: 1. Investigate the G1 phase repression function of FoxM1 in maintenance of the liver cancer stem cells. 2. Investigate the repression function of FoxM1 in HCC development and progression. 3. Investigate whether the repression function of FoxM1 is important for recovery from chronic liver injury.
Liver cancer is on the rise among the US Veterans, and it has become a challenging problem in the VA cancer clinics. That is mainly due to the fact that the available cancer drugs do not work against liver cancer. The drug resistance of liver cancer has been linked to the presence of a large number of ?stem-like? cancer cells. Studies described in this proposal will generate how those ?stem-like? cells are generated in liver cancer. Those studies will allow development of effective therapeutic approaches against this devastating disease.
|Kopanja, Dragana; Huang, Shuo; Al Raheed, Mohamed Rizwan Haroon et al. (2018) p19Arf inhibits aggressive progression of H-ras-driven hepatocellular carcinoma. Carcinogenesis 39:318-326|
|Mukhopadhyay, Nishit K; Chand, Vaibhav; Pandey, Akshay et al. (2017) Plk1 Regulates the Repressor Function of FoxM1b by inhibiting its Interaction with the Retinoblastoma Protein. Sci Rep 7:46017|
|Fantini, Damiano; Huang, Shuo; Asara, John M et al. (2017) Chromatin association of XRCC5/6 in the absence of DNA damage depends on the XPE gene product DDB2. Mol Biol Cell 28:192-200|
|Huang, Shuo; Fantini, Damiano; Merrill, Bradley J et al. (2017) DDB2 Is a Novel Regulator of Wnt Signaling in Colon Cancer. Cancer Res 77:6562-6575|
|Kopanja, Dragana; Raychaudhuri, Pradip (2016) TGF? signaling: a friend or a foe to hepatic fibrosis and tumorigenesis. Ann Transl Med 4:122|
|Kopanja, Dragana; Pandey, Akshay; Kiefer, Megan et al. (2015) Essential roles of FoxM1 in Ras-induced liver cancer progression and in cancer cells with stem cell features. J Hepatol 63:429-36|
|Wang, Zebin; Zheng, Yu; Park, Hyun Jung et al. (2013) Targeting FoxM1 effectively retards p53-null lymphoma and sarcoma. Mol Cancer Ther 12:759-67|
|Carr, Janai R; Kiefer, Megan M; Park, Hyun Jung et al. (2012) FoxM1 regulates mammary luminal cell fate. Cell Rep 1:715-29|
|Park, Hyun Jung; Gusarova, Galina; Wang, Zebin et al. (2011) Deregulation of FoxM1b leads to tumour metastasis. EMBO Mol Med 3:21-34|
|Wang, Zebin; Park, Hyun Jung; Carr, Janai R et al. (2011) FoxM1 in tumorigenicity of the neuroblastoma cells and renewal of the neural progenitors. Cancer Res 71:4292-302|
Showing the most recent 10 out of 11 publications