Michael Karin, Ph.D.
University of California, San Diego
A new study by NIEHS grantees and colleagues explains how DNA damage to liver cells can potentially lead to liver cancer. The researchers looked at CD44 proteins, which are located on the cell surface and are involved in binding with other molecules. They found that CD44 proteins may play a role in overriding the body’s natural protective response to DNA damage.
The team focused on the most common type of liver cancer — hepatocellular carcinoma (HCC). In mice exposed to toxicants known to induce HCC and in mice more prone to develop HCC, they found increased CD44 expression in precancerous and cancer cells. They also discovered that mice lacking CD44 were less likely to develop HCC.
The researchers explored how CD44 plays a role in HCC by examining its effect on p53, a tumor suppressor protein. p53 is normally activated after DNA damage to stop the damaged cells from dividing. The researchers found that p53 became inactive or was not present 2-3 days after toxicant exposure in mice with CD44. In contrast, mice that lacked CD44 still had active p53 in liver cells several days after exposure. The results indicated that CD44 may be involved in turning off the p53 response to DNA damage, which then allows the cells to continue to divide and accumulate mutations. The accumulation of mutations may lead to development of tumors.
According to the authors, these findings suggest that CD44 inhibitors or compounds that block their interactions in the cell may be potential targets for tumor prevention and therapy.
Citation: Dhar D, Antonucci L, Nakagawa H, Kim JY, Glitzner E, Caruso S, Shalapour S, Yang L, Valasek MA, Lee S, Minnich K, Seki E, Tuckermann J, Sibilia M, Zucman-Rossi J, Karin M. 2018. Liver cancer initiation requires p53 inhibition by CD44-enhanced growth factor signaling. Cancer Cell 33(6):1061–1077.