Sorafenib, a multikinase inhibitor, is considered as the only approved drug to cure the advanced hepatocellular carcinoma (HCC); however, the acquired chemoresistance caused by intratumoral hypoxia through sorafenib long term therapy induces sorafenib inefficacy. We demonstrated here that hypoxia significantly attenuated sensitivity of HCC cells to sorafenib treatment and reduced its proliferation. Autophagy was observed in sorafenib-treated HCC cells in hypoxia, and inhibition of autophagy by 3-MA eliminated hypoxia-induced sorafenib resistance. Further study revealed hypoxia-activated FOXO3a, an important cellular stress transcriptional factor, via inducing its dephosphorylation and nuclear location; and FOXO3a-dependent transcriptive activation of beclin-1 was responsible for hypoxia-induced autophagy in HCC cells. Knockout of FOXO3a inhibited the autophagy induced by sorafenib itself in normoxia and significantly enhanced the cytotoxicity of sorafenib in HCC cells; and it also inhibited the hypoxia-induced autophagy and achieved the same effect in sorafenib sensitivity-enhancement in HCC cells as it in normoxia. Finally, knockout of intratumoral FOXO3a significantly enhanced curative efficacy of sorafenib via inhibition of autophagy in xenograft tumors in nude mice. Collectively, our study suggests that FOXO3a plays a key role in regulating hypoxia-induced autophagy in sorafenib-treated HCC, and FOXO3-targeted therapy may serve as a promising approach to improve clinical prognosis of patients suffering from HCC.

As a multikinase inhibitor, sorafenib is commonly used to treat patients with advanced hepatocellular carcinoma (HCC), however, acquired resistance to sorafenib is a major obstacle to the effectiveness of this treatment. Thus, in this study, we investigated the mechanisms underlying sorafenib resistance as well as approaches devised to increase the sensitivity of HCC to sorafenib. We demonstrated that miR-124-3p.1 downregulation is associated with early recurrence in HCC patients who underwent curative surgery and sorafenib resistance in HCC cell lines. Regarding the mechanism of this phenomenon, we identified FOXO3a, an important cellular stress transcriptional factor, as the key factor in the function of miR-124-3p.1 in HCC. We showed that miR-124-3p.1 binds directly to AKT2 and SIRT1 to reduce the levels of these proteins. Furthermore, we showed that AKT2 and SIRT1 phosphorylate and deacetylate FOXO3a. We also found that miR-124-3p.1 maintains the dephosphorylation and acetylation of FOXO3a, leading to the nuclear location of FOXO3a and enhanced sorafenib-induced apoptosis. Moreover, the combination of miR-124-3p.1 mimics and sorafenib significantly enhanced the curative efficacy of sorafenib in a nude mouse HCC xenograft model. Collectively, our data reveal that miR-124-3p.1 represents a predictive indicator of early recurrence and sorafenib sensitivity in HCC. Furthermore, we demonstrate that miR-124-3p.1 enhances the curative efficacy of sorafenib through dual effects on FOXO3a. Thus, the miR-124-3p.1-FOXO3a axis is implicated as a potential target for the diagnosis and treatment of HCC.

Background: Lymph node (LN) status is vital to indicate and evaluate the curative potential of relatively early gastric cancer (GC; T1–T2) treatment (endoscopic or surgery). Currently, there is a lack of robust and convenient methods to identify such metastasis before therapeutic decision-making; therefore, there is an urgent need to identify biomarkers that could aid the identification of patients with LN metastasis. Methods: Genome-wide expression profiles of long noncoding RNA (lncRNA) in primary T1 gastric cancer data from The Cancer Genome Atlas (TCGA) was used to identify an lncRNA‑expression signature capable of detecting LN metastasis of GC, and establish a 10-lncRNA risk‑prediction model based on deap learning. The performance of the lncRNA panel in diagnosing LN metastasis was evaluated using both in silico and clinical validation methods. In silico validation was conducted using TCGA and Asian Cancer Research Group (ACRG) datasets. Clinical validation was performed on T1 and T2 patients, and the panel's efficacy was compared with that of traditional tumor markers and computed tomography (CT) scans. Results: Profiling of genome-wide RNA expression identified a panel of lncRNA to predict LN metastasis in T1 stage gastric cancer (area under the curve (AUC) = 0.961). A 10-lncRNA risk-prediction model was then constructed, which was validated successfully in T1 and T2 datasets (TCGA, AUC = 0.852; ACRG, AUC = 0.834). Thereafter, the clinical performance of the lncRNA panel was validated in clinical cohorts (T1, AUC = 0.812; T2, AUC = 0.805; T1+T2, AUC = 0.764). Notably, the 10-lncRNA panel demonstrated significantly better performance compared with CT and conventional tumor markers (carcinoembryonic antigen and carbohydrate antigen 19-9). Conclusions: The novel 10-lncRNA could diagnose LN metastasis robustly in relatively early gastric cancer (T1–T2), with promising clinical potential.

No abstract