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.
The breakthrough of immune checkpoint inhibitor (ICI) therapy has created extensive opportunities for cancer immunotherapy. Especially, the block of programmed death-1/programmed death ligand 1 (PD-L1) axis using ICIs has become a new therapeutic strategy to treat advanced gastric cancer (GC). However, in the past decade, single-arm and randomized trials for single-drug ICI therapy showed that the therapeutic effect was not satisfactory, including clinical trials for advanced GC. However, after selecting suitable predictive biomarkers and developing a combination of anti-angiogenic targeted drugs and other chemotherapeutic drugs, the objective response rate and progression-free survival of patients with gastric cancer were improved significantly. The United States Food and Drug Administration has approved treatment with pembrolizumab for patients with advanced GC with PD-L1 expression or microsatellite instability-high/mismatch repair deficiency. In this review, the updated data from the latest trial results of combination immunotherapy for GC are presented. Based on the outcome of combination therapy, we discuss its possible molecular mechanism and summarize effective predictive biomarkers. We also discuss possible problems stemming from results of other clinical trials of ICI treatment and propose other directions for ICI therapy.
Introduction FAM111B (FAM111 trypsin-like peptidase B) gene mutations have been linked to a hereditary fibrosing poikiloderma disorder known to cause poikiloderma, tendon contracture, myopathy, and pulmonary fibrosis (POIKTMP). Overexpression of FAM111B has been associated with an increased risk of certain cancers with a poor prognosis, although the relationship between FAM111B and other tumors is still unclear, and the molecular mechanism of its action is not fully understood. Methods We investigated the biological functions of FAM111B in 33 solid tumors using multi-omics data. We further recruited 109 gastric cancer (GC) patients for a clinical cohort study to confirm the effect of FAM111B on early tumor recurrence. Furthermore, we assessed the role of FAM111B in GC cell proliferation and migration via EdU incorporation, CCK8 and transwell assays in vitro. Results We found that FAM111B can enhance oncogenesis and progression in multiple tumor types. The clinical cohort of GC showed that upregulation of FAM111B is associated with early recurrence of GC, and knockdown of the FAM111B gene can inhibit the proliferation and migration of GC cells. Gene enrichment analysis indicates that FAM111B promotes cancer through immune system process, chromosome instability, DNA repair, and apoptosis regulation. Mechanistically, FAM111B appears to promote the growth cycle of malignant tumor cells while inhibiting apoptosis. Conclusion FAM111B may serve as a potential pan-cancer biomarker for predicting the prognosis and survival of malignant tumor patients. Our study elucidates the role of FAM111B in the occurrence and development of various cancers, and highlights the need for future research on FAM111B in cancers.
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.
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