Abstract
Obesity increases the risk of hepatocellular carcinoma (HCC) especially in men, but the molecular mechanism remains obscure. Here, we show that an androgen receptor (AR)-driven oncogene, cell cycle-related kinase (CCRK), collaborates with obesity-induced pro-inflammatory signaling to promote non-alcoholic steatohepatitis (NASH)-related hepatocarcinogenesis. Lentivirus-mediated Ccrk ablation in liver of male mice fed with high-fat high-carbohydrate diet abrogates not only obesity-associated lipid accumulation, glucose intolerance and insulin resistance, but also HCC development. Mechanistically, CCRK fuels a feedforward loop by inducing STAT3-AR promoter co-occupancy and transcriptional up-regulation, which in turn activates mTORC1/4E-BP1/S6K/SREBP1 cascades via GSK3β phosphorylation. Moreover, hepatic CCRK induction in transgenic mice stimulates mTORC1-dependent G−csf expression to enhance polymorphonuclear myeloid-derived suppressor cell recruitment and tumorigenicity. Finally, the STAT3-AR-CCRK-mTORC1 pathway components are concordantly over-expressed in human NASH-associated HCCs. These findings unveil the dual roles of an inflammatory-CCRK circuitry in driving metabolic and immunosuppressive reprogramming through mTORC1 activation, thereby establishing a pro-tumorigenic microenvironment for HCC development.
Highlights
Obesity increases the risk of hepatocellular carcinoma (HCC) especially in men, but the molecular mechanism remains obscure
The high-fat high-carbohydrate (HFHC)-fed female C57Bl/6 mice did not exhibit cycle-related kinase (CCRK) induction (Supplementary Fig. 1a), triglyceride/nonesterified fatty acid (NEFA) abnormalities (Supplementary Fig. 1b–c), or glucose intolerance (Supplementary Fig. 1d), the weight gain was comparable to the male counterparts (Supplementary Fig. 1e)
We found that ectopic expression of CCRK in LO2 and CCRK KO Huh[7] cells activated mTORC1 signaling as shown by increased levels of phosphorylated mechanistic target of rapamycin (mTOR) at Ser2448 (p-mTORSer2448), 4E-BP1 at Thr37/46 (p-4E-BP1Thr37/46), S6K at Thr[389] (p-S6KThr389), and the mature form of sterol regulatory element-binding protein 1 (SREBP1), which were impaired by suppression of glycogen synthase kinase 3β (GSK3β) phosphorylation at Ser[9] via over-expression of the constitutively-active S9A-GSK3β mutant (Fig. 4a)
Summary
Obesity increases the risk of hepatocellular carcinoma (HCC) especially in men, but the molecular mechanism remains obscure. Another population-based cohort study of 1.2 million Swedish men further showed that a high BMI (≥30 kg/m2) in late adolescence was associated with an increased risk of future severe liver diseases including HCC3 These findings consistently underscore the sex disparity in obesity-associated HCC, but the molecular mechanisms underlying HCC development in obese men remain obscure[4,6]. Unlike early hepatocarcinogenesis which relies on paracrine nuclear factor kappa B (NF-κB)-regulated IL-6 production by inflammatory cells[12], HCC progenitor cells in premalignant lesions acquire autocrine IL-6-STAT3 signaling to stimulate cellular proliferation and transformation[13] It is unclear how the hepatic IL-6-STAT3 cascade is activated and sustained during malignant transformation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
