Highlights d Down-regulation of ACOT12 is correlated with metastasis and poor prognosis of HCC d ACOT12 functionally suppresses HCC metastasis d ACOT12 regulates acetyl-coA metabolism and histone acetylation d Down-regulation of ACOT12 promotes HCC metastasis by epigenetic induction of TWIST2

Altered metabolism is one of the hallmarks of cancer cells. Pentose phosphate pathway (PPP) is a fundamental component of cellular metabolism. Glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP, is elevated in many cancers and contributes to tumor growth by producing ribose-5-phosphate and NADPH through PPP. However, the role of G6PD in hepatocellular carcinoma (HCC) metastasis and the clinical significance of G6PD in HCC progression and prognosis have not been well determined. In this study, by investigating tissue samples from HCC patients and HCC cell lines, we found that elevated G6PD expression is significantly associated with HCC metastasis and poor prognosis of HCCs, and that knockdown of G6PD inhibits in vitro proliferation, migration and invasion of HCC cell lines. Further studies reveal that G6PD contributes to HCC migration and invasion of hepatocellular carcinoma cells by inducing epithelial-mesenchymal transition through activation of signal transducer and activator of transcription 3 (STAT3) pathway. Our findings suggest that targeting G6PD could open up possibilities for metastasis intervention and improve the patients' outcomes for HCC.

Background Clinical outcome studies showed a high incidence of knee osteoarthritis after anterior cruciate ligament reconstruction. Abnormal joint kinematics and loading conditions were assumed as risking factors. However, little is known on cartilage contact forces after the surgery. Methods A validated computational model was used to simulate anatomic and transtibial single-bundle anterior cruciate ligament reconstructions. Two graft fixation angles (0° and 30°) were simulated for each reconstruction. Biomechanics of the knee was investigated in intact, anterior cruciate ligament deficient and reconstructed conditions when the knee was subjected to 134N anterior load and 400N quadriceps load at 0°, 30°, 60° and 90° of flexion. The tibial translation and rotation, graft forces, medial and lateral contact forces were calculated. Findings When the graft was fixed at 0°, the anatomic reconstruction resulted in slightly larger lateral contact force at 0° compared to the intact knee while the transtibial technique led to higher contact force at both 0° and 30° under the muscle load. When graft was fixed at 30°, the anatomic reconstruction overstrained the knee at 0° with larger contact forces, while the transtibial technique resulted in slightly larger contact forces at 30°. Interpretation This study suggests that neither the anatomic nor the transtibial reconstruction can consistently restore normal knee biomechanics at different flexion angles. The anatomic reconstruction may better restore anteroposterior stability and contact force with the graft fixed at 0°. The transtibial technique may better restore knee anteroposterior stability and articular contact force with the graft fixed at 30° of flexion.