The association between type 2 diabetes (T2D) and hepatocellular carcinoma (HCC) is of great public health concern, not only because T2D is associated with elevated risks for many cancers, but also due to increasing global T2D prevalence and limited therapies for HCC. We demonstrate that heterozygous deletion of the Ncoa5 gene causes spontaneous development of HCC, exclusively in male mice. Tumor development is preceded by increased IL-6 expression, early-onset glucose intolerance, and progressive steatosis and dysplasia in livers. Blockading IL-6 overexpression averts glucose intolerance and partially deters HCC development. Moreover, reduced Ncoa5 expression is associated significantly with human HCC and HCC with comorbid T2D. These findings implicate the coexistence of T2D and HCC not as an epiphenomenon, but rather that these two diseases share a common pathogenic mechanism controlled by Ncoa5. Our results demonstrate that Ncoa5 haplo-insufficiency activates a pathogenic pathway concomitantly leading to impaired glucose tolerance and HCC development in mice. These results reveal Ncoa5 haplo-insufficiency as a genetic link between T2D and HCC. Moreover, our Ncoa5+/- mouse model of glucose intolerance with comorbid HCC provides an ideal platform for studying the molecular basis and therapeutic responsiveness of HCC with comorbid T2D. Thus, our findings open new avenues for developing therapeutic approaches to combat these diseases.
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