No abstract

Rationale: Hepatocellular carcinoma (HCC) is an aggressive malignant solid tumor wherein CDK1/PDK1/β-Catenin is activated, suggesting that inhibition of this pathway may have therapeutic potential.Methods: CDK1 overexpression and clinicopathological parameters were analyzed. HCC patient-derived xenograft (PDX) tumor models were treated with RO3306 (4 mg/kg) or sorafenib (30 mg/kg), alone or in combination. The relevant signaling of CDK1/PDK1/β-Catenin was measured by western blot. Silencing of CDK1 with shRNA and corresponding inhibitors was performed for mechanism and functional studies.Results: We found that CDK1 was frequently augmented in up to 46% (18/39) of HCC tissues, which was significantly associated with poor overall survival (p=0.008). CDK1 inhibitor RO3306 in combination with sorafenib treatment significantly decreased tumor growth in PDX tumor models. Furthermore, the combinatorial treatment could overcome sorafenib resistance in the HCC case #10 PDX model. Western blot results demonstrated the combined administration resulted in synergistic down-regulation of CDK1, PDK1 and β-Catenin as well as concurrent decreases of pluripotency proteins Oct4, Sox2 and Nanog. Decreased CDK1/PDK1/β-Catenin was associated with suppression of epithelial mesenchymal transition (EMT). In addition, a low dose of RO3306 and sorafenib combination could inhibit 97H CSC growth via decreasing the S phase and promoting cells to enter into a Sub-G1 phase. Mechanistic and functional studies silencing CDK1 with shRNA and RO3306 combined with sorafenib abolished oncogenic function via downregulating CDK1, with downstream PDK1 and β-Catenin inactivation.Conclusion: Anti-CDK1 treatment can boost sorafenib antitumor responses in PDX tumor models, providing a rational combined treatment to increase sorafenib efficacy in the clinic.

Background: The value of alpha-fetoprotein (AFP) as a prognostic indicator in patients with hepatocellular carcinoma (HCC) has been proposed in recent studies, but the evidence so far is still contradictory. This analysis aims to evaluate the prognostic value of preoperative AFP level in patients undergoing curative resection. Methods: This retrospective study reviewed the prospectively collected data of all patients who underwent initial liver resection for HCC at Queen Mary Hospital during the period from March 1999 to March 2013. Patients with palliative resection, positive margin after pathological examination or distant metastasis were excluded from the study. Survival of patients with AFP level of <20, 20-400 and >400 ng/mL were compared with Kaplan-Meier analysis. Subgroup analysis was performed according to tumour stage (7 th edition UICC staging) and tumour size. The optimal cutoff value was determined by area under receiver operating characteristic curve. Results: A total of 1,182 patients were included. Best overall (OS) and disease free survival (DFS) was observed in patients with AFP level <20 ng/mL. Progressively worse outcomes were seen for patients with increasing level of AFP. The median OS were 132.9, 77.2 and 38.4 months for patients with AFP <20, 20-400 and >400 ng/mL respectively (P<0.001). The median DFS for these three groups were 55.6, 25 and 8.4 months respectively (P<0.001). There was significant difference in both OS and DFS among all 3 groups. With subgroup analysis according to tumour stage (stage I and II versus stage III and IV) and tumour size (5 cm or less versus larger than 5 cm), such difference was still observed and remained statistically significant. Optimal cutoff value by discriminant analysis was 12,918.3 ng/mL for OS and 9,733.3 ng/mL for DFS. Conclusions: This study demonstrates that AFP is a significant prognostic indicator in HCC. Despite tumour stage and size, high level of AFP is associated with poorer OS and DFS. Whether the level of AFP should be included in current staging systems, or treatment protocols, is yet to be determined.