Background: Lenvatinib (LEN) combined with anti-PD-1 antibodies (PD-1) exerted promising effects on unresectable hepatocellular carcinoma (uHCC). We assessed the safety and clinical efficacy of triple therapy [LEN+PD-1+transcatheter arterial chemoembolization (TACE)] in uHCC. Methods: uHCC patients with an ECOG PS score of 0– 1 and Child–Pugh class A who underwent triple therapy were included. The primary endpoint was objective response rate (ORR) based on mRECIST. Secondary endpoints were conversion rate to liver resection and treatment-related adverse events. Results: Between November 2018 and December 2020, 62 uHCC patients who underwent triple therapy at four major cancer centers in China were analyzed, including 35 in BCLC-C, 21 in BCLC-B, and 6 in BCLC-A. With a median follow-up of 12.2 months (range, 7.6– 33.3 months), the investigator and blinded independent central review-assessed ORR were 80.6% and 77.4%, respectively. A total of 33 patients (53.2%) reached the standard of conversion to resectable HCC and 29 patients underwent resection. The median interval between start of triple therapy and resection was 123 days (range, 55– 372 days). Pathological complete response and major pathological response were observed in 16 and 24 patients, respectively. Median overall survival and progression-free survival were not reached. Treatment-related adverse events occurred in 74.2% of the patients (grade ≥ 3, 14.5%; grade ≥ 4, 4.8%). Conclusion: Combination of LEN, PD-1 and TACE showed a high rate of tumor response and convert resection in uHCC patients, with manageable toxicity.

Long non-coding RNAs are involved in the pathology of various tumors, including hepatocellular carcinoma. The expression of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is increased in numerous types of tumors and is involved in tumor cell proliferation, migration, invasion and apoptosis. MALAT1 level was reported to be upregulated in hepatocellular carcinoma tissues, but its roles and the specific molecular mechanisms are still unclear. The expression of MALAT1 and miR-142-3p in hepatocellular carcinoma tissues, cell lines and adjacent non-tumor tissues was assessed by Q-PCR. The putative-binding sites between MALAT1 and miR-142-3p were predicted by bioinformatics analysis. The expression of MALAT1 in HepG2 and SMMC-7721 cells was knocked down by transfection with MALAT1 siRNAs. Cell viability was assessed by the Cell Counting Kit-8 (CCK-8) assay after the indicated transfection in HepG2 and SMMC-7721 cells. Cell proliferation was assessed by EdU assay, and cell apoptosis was explored by flow cytometry. The migration and invasion potency of HepG2 and SMMC-7721 cells was assessed by the cell migration assay and matrigel invasion assay. Protein level of vimentin, E-cadherin and SMAD5 were assessed by Western blot. Overexpressed MALAT1 acts as a competing endogenous RNA sponge for miR-142-3p in hepatocellular carcinoma. The knockdown of MALAT1 inhibited the proliferation, migration, invasion, and epithelial cell-to-mesenchymal transition (EMT), and promoted apoptosis of hepatocellular carcinoma cells via miR-142-3p. MiR-142-3p inhibited cell proliferation, migration, invasion and EMT, and promoted the cell apoptosis by targeting SMAD5 in hepatocellular carcinoma. MALAT1 promoted tumor growth by regulating the expression of miR-142-3p in vivo. MALAT1 promoted cell proliferation, migration, and invasion of hepatocellular carcinoma cells by antagonizing miR-142-3p.

Purpose Retinol metabolism is intricately linked to the occurrence and progression of hepatocellular carcinoma (HCC); however, the precise pathogenic relationship between them remains elusive. The aim of this study was to elucidate the characteristics of retinol metabolism in HCC through Mendelian randomization, prognostic model and experimental validation. Methods We used transcriptomic data related to HCC in TCGA and GEO databases for a variety of machine learning, including differential gene expression analysis, functional enrichment analysis, protein–protein network interaction, ceRNA regulatory network, and single-cell sequencing analysis. Mendelian randomization analysis was used to elucidate the causal analysis of retinol metabolism and the occurrence of HCC. Consensus cluster analysis was performed based on 11 retinol metabolism-related genes, and the prognostic model was constructed by Lasso regression and Cox regression analysis. The expression level of RDH16 gene was detected in cell lines and clinical samples, and finally the function of RDH16 gene and its regulatory relationship with miR- 665 were verified by in vitro cell experiments. Results Differentially expressed genes were mainly concentrated in the retinol metabolic pathway. Mendelian randomization analysis showed that decreased retinol metabolic activity was causally associated with the occurrence of HCC. RDH16 gene was significantly lower expressed in HCC, and inhibition of RDH16 gene expression could promote the proliferation, migration and invasion of HCC cells and inhibit cell apoptosis. miR- 665 is an upstream regulator of RDH16 gene, which can inhibit the expression and function of RDH16. Conclusion The decrease of retinol metabolic activity can promote the occurrence and development of HCC. Targeting retinol metabolic pathway may be a new direction for the treatment of HCC.

Circular RNAs (circRNAs) have been confirmed to be associated with the progression of various cancers, including hepatocellular carcinoma (HCC). However, the role and mechanism of circHIPK3 in HCC are still unclear. To investigate its function, circHIPK3 expression was first determined by RT–qPCR in HCC tissues or cells. Functionally, cell proliferation and invasion were investigated by CCK-8, EdU, or Transwell assays. In terms of understanding the mechanism, the interaction of the circRNA HIPK3/micro RNA 124 (miRNA 124) or micro RNA 506 (miRNA506) /PDK2 regulatory loop was verified by dual-luciferase reporter gene assay. In addition, a xenograft tumor model was established to confirm the impact of circHIPK3 on the growth of HCC cells in vivo. We found that circHIPK3 was upregulated in HCC patients and associated with clinical characteristics, while miR-124 and miR-506 were downregulated in HCC patients. Additionally, we proved that knock down of circHIPK3 remarkably suppressed the proliferation and invasion of HCC cells. Mechanistically, circHIPK3 directly bound to miR-124 or miR-506 and inhibited their expression, and PDK2 was a target gene of miR-124 or miR-506. Moreover, circHIPK3 overexpression reversed the inhibitory effect of miR-124 or miR-506 on HCC progression. miR-124 or miR-506 could also suppress tumorigenesis of HCC cells by PDK2. Furthermore, in vivo evidence confirmed that knock down of circHIPK3 inhibited tumor formation. We suggest that circHIPK3 can accelerate the proliferation and invasion of HCC cells by sponging miR-124 or miR-506 to upregulate PDK2, which is the underlying mechanism of circHIPK3-induced HCC progression.

Background: This study aimed to determine whether salvage hepatectomy offers prognostic advantages for unresectable hepatocellular carcinoma (uHCC) patients with clinical complete response (cCR) after conversion therapy. Methods: A total of 74 consecutive uHCC patients with cCR after conversion therapy at seven major cancer centers in China between October 2018 and December 2021 were included. One-to-one propensity score matching (PSM) was performed to minimize the influence of potential confounders. Disease-free survival (DFS) and overall survival (OS) rates were compared between the surgical group and the non-surgical group. Results: Before PSM, 45 patients received salvage hepatectomy, and 29 patients received nonsurgical treatment. The 1-, 2-, and 3-year DFS rates were 77.8%, 61.5%, and 61.5% in the surgical group and 81.2%, 60.9%, and 60.9% in the non-surgical group, respectively. The 1-, 2-, and 3-year OS rates were 92.9%, 92.9%, and 69.7% in the surgical group and 100%, 70%, and 70% in the non-surgical group, respectively. There were no statistical differences in DFS and OS between groups [hazard ratio (HR)=0.715, 95% confidence interval (CI): 0.250– 2.043, p=0.531; HR=0.980, 95% CI: 0.177– 5.418, p=0.982, respectively]. After PSM, 26 pairs of patents were selected; there remained no significant differences in DFS and OS between these two groups (HR=1.547, 95% CI: 0.512– 4.669, p=0.439; HR=1.024, 95% CI: 0.168– 6.242, p=0.979, respectively). Conclusion: Through the study, it tend to show that salvage hepatectomy may be not essential for uHCC patients with cCR, especially for patients with a high risk of surgical complications. Prospective trials with long term follow-up are warranted to evaluate this treatment option. Plain Language Summary: To date, there is limited evidence on the prognosis of the unresectable hepatocellular carcinoma (uHCC) patients with clinical complete response (cCR), and the necessity of salvage surgery remains controversial. In this study, they compare and evaluate therapeutic benefits of salvage hepatectomy and nonsurgical treatment in the management of uHCC patients with cCR after conversion therapy. Finally, a total of 74 consecutive uHCC patients with cCR after conversion therapy at seven major cancer centers in China were included. There were no statistically significant differences for disease-free survival and overall survival were observed before and after propensity score matching. They revealed that cCR after conversion therapy led to a good prognosis for patients with uHCC. Furthermore, nonsurgical treatment provided similar survival benefits to those of salvage hepatectomy, suggesting that salvage hepatectomy may be not essential for uHCC patients with cCR.