In recent years, a growing body of evidence has provided support for the important role of microRNAs (miRNAs) in the progression of human cancers. A recent study showed that a novel miRNA miR-3650 expression was significantly decreased in hepatocellular carcinoma (HCC). However, the precise role of miR-3650 in HCC have remained poorly understood. In this study, we found that miR-3650 expression was frequently decreased in HCC tissues. Low expression of miR-3650 is positively associated with tumor metastasis and poor survival of HCC patients. Forced expression of miR-3650 significantly inhibited the migration and epithelial-mesenchymal transition (EMT) of HCC cells. Through bioinformatic analysis and luciferase assays, we confirmed that neurofascin (NFASC) is a directly target mRNA of miR-3650. Rescue experiment demonstrated that NAFSC overexpression could partially counteracted the inhibitory effect of miR-3650 in HCC metastasis and EMT. In conclusion, our findings are the first time to demonstrate that reduced expression of miR-3650 in HCC was correlated with tumor metastasis and poor survival. MiR-3650 repressed HCC migration and EMT by directly targeting NFASC. Our findings suggested that miR-3650 may serve as a potential prognostic marker and promising application in HCC therapy.

Purpose: This study aimed to assess the efficacy and safety of combining transarterial chemoembolization (TACE) with lenvatinib and a PD-1 inhibitor (TACE+LEN+PD-1) compared to TACE combined with lenvatinib alone (TACE+LEN) in intermediate-stage hepatocellular carcinoma (HCC) patients exceeding the up-to-7 criteriaMaterials and methods: Data from 115 patients with intermediate-stage HCC exceeding the up-to-7 criteria, treated between January 2015 and December 2023, were prospectively collected and retrospectively analyzed. Key clinical outcomes, including overall survival (OS), progression-free survival (PFS), tumor response rates based on modified Response Evaluation Criteria in Solid Tumors (mRECIST), and adverse events (AEs), were evaluated and compared between the two treatment groups. Univariate and multivariate analyses were performed to identify factors affecting OS and PFS.Results: Among the patients, 35 received TACE+LEN+PD-1, and 80 underwent TACE+LEN. The TACE+LEN+PD-1 group achieved a longer median PFS (10.0 months vs. 5.7 months; P=0.002) and a median OS of 21.0 months, compared to 16.2 months in the TACE+LEN group, though the OS difference was not statistically significant (P=0.096). Progression to macrovascular invasion (MVI) or extrahepatic spread (EHS) was delayed in the TACE+LEN+PD-1 group compared to the TACE+LEN group (12.0 months vs. 7.5 months; P=0.007). Multivariate analysis identified treatment modality and tumor burden score (TBS) as independent prognostic factors for OS and PFS. Subgroup analyses showed that patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or HBV positivity derived greater benefits from TACE+LEN+PD-1, while those with high TBS or a Child-Pugh score of 7 did not show similar advantages. The rates and severity of AEs were comparable between groups (any grade: 88.6% vs. 91.3%, P=0.733; grade 3 or 4: 48.6% vs. 42.5%, P=0.546).Conclusion: TACE+LEN+PD-1 significantly improved PFS, particularly by delaying progression to MVI or EHS after the first TACE session in intermediate-stage HCC patients exceeding the up-to-7 criteria, compared to TACE+LEN. Subgroup analysis indicated superior survival benefits for patients with a PS of 0 or HBV positivity, but not in those with high TBS or a Child-Pugh score of 7. The safety profile of TACE+LEN+PD-1 was comparable to TACE+LEN. However, the OS benefit between the two groups was not statistically significant.

The primary problem associated with fibrosarcoma is its high potential to metastasize to the lung. Aberrant expression of SAPCD2 has been widely reported to be implicated in the progression and metastasis in multiple cancer types. However, the clinical significance and biological roles of SAPCD2 in fibrosarcoma remain unknown. Here, we reported that SAPCD2 expression was markedly elevated in fibrosarcoma tissues, and its expression was differentially upregulated in fibrosarcoma cell lines compared with that in several primary fibroblast cell lines. Kaplan-Meier survival analysis revealed that SAPCD2 overexpression was significantly correlated with early progression and metastasis, and poor prognosis in fibrosarcoma patients. Our results further showed that silencing SAPCD2 inhibited the proliferation and increased the apoptosis of fibrosarcoma cells in vitro. Importantly, silencing SAPCD2 repressed lung metastasis of fibrosarcoma cells in vivo. Mechanistic investigation further demonstrated that silencing SAPCD2 inhibited the proliferation and lung metastasis of fibrosarcoma cells by activating the Hippo signaling pathway, as evidenced by the finding that constitutively active YAP1, YAP1-S127A, significantly reversed the inhibitory effect of SAPCD2 downregulation on the colony formation and anchorage-independent growth capabilities of fibrosarcoma cells, as well as the stimulatory effect on the apoptotic ratio of fibrosarcoma cells. In conclusion, SAPCD2 promotes the proliferation and lung metastasis of fibrosarcoma cells by regulating the activity of Hippo signaling, and this mechanism represents a potential therapeutic target for the treatment of lung metastatic fibrosarcoma.

Background. Transarterial chemoembolization (TACE) is recommended for intermediate-stage HCC patients. Owing to substantial variation in its efficacy, indicators of patient responses to TACE need to be determined. Methods. A Gene Expression Omnibus (GEO) dataset consisting of patients of different TACE-response status was retrieved. Differentially expressed genes (DEGs) were calculated and variable gene ontology analyses were conducted. Potential drugs and response to immunotherapy were predicted using multiple bioinformatic algorithms. We built and compared 5 machine-learning models with finite genes to predict patients response to TACE. The model was also externally validated to discern different survival outcomes after TACE. Tumor-infiltrating lymphocytes (TILs) and tumor stemness index were evaluated to explore potential mechanism of our model. Results. The gene set variation analysis revealed enhanced pathways related to G2/M checkpoint, E2F, mTORC1, and myc in TACE nonresponders. TACE responders had better immunotherapy response too. 373 DEGs were detected and the upregulated DEGs in nonresponders were enriched in IL-17 signal pathway. 5 machine-learning models were constructed and evaluated, and a linear support vector machine (SVM)-based model with 10 genes was selected (AQP1, FABP4, HERC6, LOX, PEG10, S100A8, SPARCL1, TIAM1, TSPAN8, and TYRO3). The model achieved an AUC and accuracy of 0.944 and 0.844, respectively, in the development cohort. In the external validation cohort comprised of patients receiving adjuvant TACE and postrecurrence TACE treatment, the predicted response group significantly outlived the predicted nonresponse counterparts. TACE nonresponders tend to have more macrophage M0 cells and lower resting mast cells in the tumor tissue and the stemness index is also higher than responders. Those characteristics were successfully captured by our model. Conclusion. The model based on expression data of 10 genes could potentially predict HCC patients response and prognosis after TACE treatment. The discriminating power was TACE-specific.