Oncogene identified as a therapeutic target for liver cancer

By Samantha Black, Ph.D.

August 22, 2019 -- The function of an enzyme that is highly expressed in many cancers has been revealed to regulate key pathways in cancer metabolic adaptation. Researchers at the Georgia Cancer Center and Medical College of Georgia at Augusta University published their findings in Hepatology.

The incidence of liver cancer has tripled in the United States since 1980, according to the American Cancer Society, and the condition is three times more common in males. Liver cancer death rates have also increased, just over 2 percent per year since 2007, and it's a leading cause of death worldwide.

Cancer cells must efficiently coordinate glycolysis and glutaminolysis to satisfy both bioenergetic and synthetic requirements for their proliferation and survival, and these are characteristically altered during cancer metabolic reprogramming. This reprogramming typically occurs through dysregulation and hyperactivation of proliferative signaling pathways, and loss of tumor suppression function. Hyperactivated phosphoinositide 3-kinase (PI3K)/Akt serine/threonine kinase (Akt) and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathways play central roles in cancer cell metabolic adaptation given that their downstream effectors, such as Akt and c-Myc, control most of the glycolytic and glutaminolysis genes. Moreover, tumor suppressor p53 and phosphatase and tensin homolog (PTEN) is often inactivated or lost in most cancer. These molecules normally negatively regulate activation of PI3K/Akt and MAPK/ERK pathways and suppress metabolic adaptation. However, in the case of liver cancer, they are unable to block metabolic reprogramming.

NAD(P)H quinone dehydrogenase 1 (Nqo1) is a cytosolic flavoprotein. This FAD-binding protein forms homodimers and reduces quinones to hydroquinones. Under normal conditions, Nqo1 eliminates free radicals inside cells, but may function differently during cancer where expression is high. Nqo1 is highly expressed in many cancers including liver, breast, pancreas, ovarian, and thyroid. Free radicals can aid in cancer development and because Nqo1 has been found at high levels in many cancers, it is thought to help cancer proliferation, although not specifically determined in the current study. Therefore, Nqo1 may be a good therapeutic target for the treatment of liver and other types of cancer.

Research in this study began by comparing normal mouse livers to cancerous mouse livers to identify which genes are upregulated. Diethylnitrosamine-induced Hepatocellular carcinoma (DEN-induced HCC) was used to induce liver cancer in mice. RNA-sequencing (RNA-Seq) was used to compare nontumorous normal livers versus DEN chemical-induced liver tumors in mice. The Nqo1 gene was knocked out to determine the effect that the enzyme has on liver cancer and compared using xenographs in Nqo1-/- and Nqo1+/- mice. Nqo1 was found to be highly expressed and researchers correlated this expression to increased tumor size and decreased patient survival. Moreover, scientists found that knocking out Nqo1 blocks the metabolic adaptation needed to enable liver cancer cell proliferation. Ultimately, this study provides more evidence of Nqo1's function as an oncogene.

"Somehow these pathways are also interacting with each other via different target genes," Dr. Manali Dimri, a MCG postdoctoral fellow, says. "And, eventually, they are working together for cell proliferation, migration and metabolism."

Future steps in this research include screening existing drugs to access if any are successful in suppressing Nqo1. Several have already been tested, but are very good at suppressing enzymatic activity, but not impacting cancer’s ability to replicate. Nevertheless, once a drug has been identified, the MCG researchers will be ready to develop the therapy to treat liver cancer!



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