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ARS Home » Northeast Area » Beltsville, Maryland (BARC) » Beltsville Agricultural Research Center » Animal Biosciences & Biotechnology Laboratory » Research » Publications at this Location » Publication #303972
Title: Gene expression profiling of MYC-driven tumor signatures in porcine liver stem cells by transcriptome sequencing

Author
item Talbot, Neil
item ARAVALLI, RAJAGOPAL - University Of Minnesota
item STEER, CLIFFORD - University Of Minnesota

Submitted to: Hepatology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/15/2014
Publication Date: 2/21/2015
Citation: Talbot, N.C., Aravalli, R.N., Steer, C.J. 2015. Gene expression profiling of MYC-driven tumor signatures in porcine liver stem cells by transcriptome sequencing. Hepatology. 21(7):2011-29.

Interpretive Summary: It is now well-established that cancer stem cells (CSCs) drive tumor growth and that the cancer gene, c-Myc, plays a critical role in converting cells to CSCs. However, little is known about the genes that are induced and regulated by c-Myc to generate tumors, and, in particular, tumors of the liver. In this study, an immortal porcine liver stem cell line, PICM-19, was used to study the role of c-Myc in producing liver cancer. Gene expression caused by the artificial expression of c-Myc in the PICM-19 liver stem cells was determined by RNA sequencing. The results showed that c-Myc-overexpressing PICM-19 cells formed tumors in immunodeficient mice demonstrating that in appropriate expression of the c-Myc gene was sufficient to convert them into cancer cells (PICM-19-CSCs). By using comparative bioinformatics analyses, it was determined that > 1000 genes were expressed differently in the PICM-19-CSCs compared with the normal PICM-19 cells. Gene function analysis showed that the c-Myc-induced gene expression was involved with metabolism, cell adhesion, cell growth and proliferation, inflammation and various tumor-related properties. Six genes expressed by PICM-19 cells (CDO1, C22orf39, DKK2, ENPEP, GPX6, SRPX2) were completely silenced in the PICM-19-CSCs, suggesting that these genes may be critical in inducing tumors. In addition, the gene expression profile of PICM-19-CSCs had significant similarities to that of CSCs isolated from human hepatocellular carcinomas (HCC). The c-Myc-driven genes identified in this study may serve as promising candidates for the development of targeted HCC therapies that would not damage non-cancerous stem cells or other normal cells present in the liver.

Technical Abstract: It is now well-established that cancer stem cells (CSCs) drive tumor growth and that the cancer gene, c-Myc, plays a critical role in converting cells to CSCs. However, little is known about the genes that are induced and regulated by c-Myc to generate tumors, and, in particular, tumors of the liver. In this study, an immortal porcine liver stem cell line, PICM-19, was used to study the role of c-Myc in producing liver cancer. Gene expression caused by the artificial expression of c-Myc protein in the PICM-19 liver stem cells was determined. The results showed that PICM-19 cells with an increased abundance of c-Myc protein formed tumors in immunodeficient mice demonstrating that inappropriate levels of the c-Myc protein was sufficient to convert them into cancer cells (PICM-19-CSCs). It was determined that the expression level of more than 1000 genes was changed in the PICM-19-CSCs compared with the normal PICM-19 cells. Categorization of the genes by function showed that the genes whose expression was altered by c-Myc were involved with metabolism, cell adhesion, cell growth and proliferation, inflammation and various tumor-related properties. The expression of six genes expressed by normal PICM-19 cells were not detected in the PICM-19-CSCs, suggesting that these genes may be critical in inducing tumors. In addition, the gene expression profile of PICM-19-CSCs had significant similarities to that of CSCs isolated from a human liver cancer, hepatocellular carcinoma. The c-Myc-regulated genes identified in this study may serve as promising candidates for the development of targeted hepatocellular carcinoma therapies that would not damage non-cancerous stem cells or other normal cells present in the liver.