COLUMBUS, Ohio – As liver cancer develops, tumor cells lose the ability to
produce and release glucose into the bloodstream, a key function of healthy
liver cells for maintaining needed blood-sugar levels.
The findings come from a study by scientists at The Ohio State
Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J.
Solove Research Institute (OSUCCC – James).
The loss of this type of glucose production, a process called
gluconeogenesis, is caused by the over-expression of a molecule called
microRNA-23a. The change might aid cancer-cell growth and proliferation by
helping to maintain high levels of glycolysis under conditions of drastically
reduced mitochondrial respiration, also known as the Warburg effect.
The findings suggest that suppressing miR-23a might reverse this process
and offer a new treatment for hepatocellular carcinoma (HCC), the most
common form of liver cancer.
“This study identifies an important mechanism that severely blocks glucose
production and its release from the liver as liver cells transform into cancer
cells,” says principal investigator Dr. Samson Jacob, professor of molecular and
cellular biochemistry and William and Joan Davis Professor in Cancer Research,
Division of Hematology and Oncology at Ohio State and co-leader of the OSUCCC –
James Experimental
Therapeutics Program. “It is conceivable that delivery of an anti-miR23a to
the tumor site could reverse this.”
For this study, Jacob and his colleagues used an animal model that develops
diet-induced HCC, along with primary-tumor samples from patients and HCC cell
lines. The mouse model mimics different stages of human hepatocarcinogenesis.
Key findings include:
- Levels of enzymes in the gluconeogenesis pathway were drastically reduced, along with transcription factors involved in the expression of the genes encoding those enzymes.
- miR-23a expression was significantly up-regulated in the animal model and in primary human HCC.
- miR-23a suppresses the enzyme glucose-6-phosphatase and the transcription factor PGC-1a, two important components of the gluconeogenesis pathway.
- Interleukin-6 and Stat-3 signaling cause the upregulation of miR-23a.
“Based on our data,” Jacob says, “we conclude that gluconeogenesis is
severely compromised in HCC by IL6-Stat3-mediated activation of miR-23a, which
directly targets and suppresses glucose-6-phosphatase and PGC-1a, leading to
decreased glucose production in HCC.”
Jacob notes that since glucose-6-phosphatase is also essential for liver
cells to convert glycogen (the storage form of glucose) to glucose, suppression
of this enzyme can block all pathways leading to glucose production by the
liver.
Funding from the NIH/National Cancer Institute (grants CA086978) and NIH/National Institute
of Diabetes and Digestive and Kidney Diseases (grant DK088076) supported this
research.
Other Ohio State researchers involved in this study were Bo Wang, Shu-Hao
Hsu, Wendy Frankel and Kalpana Ghoshal.
The Ohio State University Comprehensive Cancer
Center – Arthur G. James Cancer Hospital and Richard J. Solove Research
Institute strives to create a cancer-free world by integrating scientific
research with excellence in education and patient-centered care, a strategy that
leads to better methods of prevention, detection and treatment. Ohio State is
one of only 41 National Cancer Institute (NCI)-designated
Comprehensive Cancer Centers and one of only seven centers funded by the NCI to
conduct both phase I and phase II clinical trials. The NCI recently rated Ohio
State’s cancer program as “exceptional,” the highest rating given by NCI survey
teams. As the cancer program’s 210-bed adult patient-care component, The James
is a “Top Hospital” as named by the Leapfrog Group and one of the top 20 cancer
hospitals in the nation as ranked by
U.S.News & World Report.
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Contact: Darrell E. Ward, Medical Center Public Affairs and Media
Relations,
614-293-3737, or Darrell.Ward@osumc.edu
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