The tumor microenvironment (TME) is a complex multicellular functional compartment that includes fibroblasts, myofibroblasts, endothelial cells, immune cells, and extracellular matrix (ECM) elements. The microenvironment provides an optimum condition for the initiation, growth, and dissemination of hepatocellular carcinoma (HCC). As one of the critical and abundant components in tumor microenvironment, cancer-associated fibroblasts (CAFs) have been implicated in the progression of HCC. Through secreting various growth factors and cytokines, CAFs contribute to the ECM remodeling, stem features, angiogenesis, immunosuppression, and vasculogenic mimicry (VM), which reinforce the initiation and development of HCC. In order to restrain the CAFs-initiated HCC progression, current strategies include targeting specific markers, engineering CAFs with tumor-suppressive phenotype, depleting CAFs’ precursors, and repressing the secretions or downstream signaling. In this review, we update the emerging understanding of CAFs in HCC, with particular emphasis on cellular origin, phenotypes, biological functions and targeted strategies. It provides insights into the targeting CAFs for HCC treatment.

The senescence of mesenchymal stem cells (MSCs) plays a crucial role in the development and progression of systemic lupus erythematosus (SLE). Exosomes, small spherical bilayer proteolipid vesicles, contribute to the communication between various cells and their microenvironment by transferring information via their cargo, including the proteins, lipids, and RNAs. While exosomal miRNAs participate in various biological activities, correlations of circulating exosomes with senescent signs of BM-MSCs remain unclear. In our study, we aimed at exploring the roles of circulating exosomal miRNAs in the senescence of MSCs. We found that exosomes derived from SLE serum could increase the proportions of SA-β-gal positive cells, disorganize cytoskeletons, and reduce growth rates. Moreover, the expression of miR-146a declined significantly in serum exosomes of SLE patients compared with healthy controls. miR-146a could be internalized into MSCs via exosomes and participate in MSCs senescence through targeting TRAF6/NF-κB signaling. These results clarified the novel mechanism of MSCs senescence in SLE patients.

Purpose: N6-methyladenosine (m⁶A) RNA methylation has been implicated in various malignancies. This study aimed to identify the m⁶A methylation regulator-based prognostic signature for hepatocellular carcinoma (HCC) as well as provide candidate targets for HCC treatment.Methods: The least absolute shrinkage and selection operator (LASSO) analyses were performed to identify a risk signature in The Cancer Genome Atlas (TCGA) datasets. The risk signature was further validated in International Cancer Genome Consortium (ICGC) and Pan-Cancer Analysis of Whole Genomes (PCAWG) datasets. Following transfection of short hairpin RNA (shRNA) targeting YTHDF1, the biological activities of HCC cells were evaluated by Cell Counting Kit-8 (CCK-8), wound-healing, Transwell, flow cytometry, and xenograft tumor assays, respectively. The potential mechanisms mediated by YTHDF1 were predicted by overrepresentation enrichment analysis (ORA)/gene set enrichment analysis (GSEA) and validated by Western blotting.Results: Overexpression of m⁶A RNA methylation regulators was correlated with malignant clinicopathological characteristics of HCC patients. The Cox regression and LASSO analyses identified a risk signature with five m⁶A methylation regulators (KIAA1429, ZC3H13, YTHDF1, YTHDF2, and METTL3). In accordance with HCC cases in TCGA, the prognostic value of risk signature was also determined in ICGC and PCAWG datasets. Following analyzing the expression and clinical implications in TCGA and Gene Expression Omnibus (GEO), YTHDF1 was chosen for further experimental validation. Knockdown of YTHDF1 significantly inhibited the proliferation, migration, and invasion of HCC cells, as well as enhanced the apoptosis in vitro. Moreover, silencing YTHDF1 repressed the growth of xenograft tumors in vivo. Mechanism investigation indicated that YTHDF1 might promote the aggressive phenotypes by facilitating epithelial–mesenchymal transition (EMT) and activating AKT/glycogen synthase kinase (GSK)-3β/β-catenin signaling.Conclusion: The current study identified a robust risk signature consisting of m⁶A RNA methylation regulators for HCC prognosis. In addition, YTHDF1 was a potential molecular target for HCC treatment.

Overexpression of Flap endonuclease 1 (FEN1) has been previously implicated in hepatocellular carcinoma (HCC), while its expression features and mechanisms remain unclear. In the current study, differential expression genes (DEGs) were screened in HCC tissues and normal liver tissues in 4 Gene Expression Omnibus (GEO) datasets. FEN1, one of the hub co-overexpressed genes, was further determined overexpressed in HCC tissues in TCGA, local HCC cohorts, and hepatocarcinogenesis model. In addition, high expression of FEN1 indicated poor prognosis of HCC patients. Loss-of-function and gain-of-function assays demonstrated that FEN1 enhanced the proliferation, cell cycle phage transition, migration/ invasion, therapy resistance, xenograft growth, and epithelial-mesenchymal transition (EMT) process of HCC cells. Mechanically, FEN1 could inactivate P53 signaling by preventing the ubiquitination and degradation of mouse double minute 2 (MDM2) via recruiting ubiquitin-specific protease 7 (USP7). Interfering USP7 with P22077 significantly reversed the malignant phenotypes activated by FEN1. In conclusion, this study suggests FEN1 as a robust prognostic biomarker and potential target for HCC.

Hepatocellular carcinoma (HCC) is a common gastrointestinal malignancy with a leading incidence of cancer-related mortality worldwide. Despite the progress of treatment options, there remains low efficacy for patients with intermediate-advanced HCC, due to tumor metastasis, recurrence and chemoresistance. Increasing evidence suggests that exosomes in the tumor microenvironment (TME), along with other extracellular vesicles (EVs) and cytokines, contribute to the drug chemosensitivity of cancer cells. Exosomes, the intercellular communicators in various biological activities, have shown to play important roles in HCC progression. This review summarizes the underlying associations between exosomes and chemoresistance of HCC cells. The exosomes derived from distinct cell types mediate the drug resistance by regulating drug efflux, epithelial-mesenchymal transition (EMT), cancer stem cell (CSC) properties, autophagic phenotypes, as well as the immune response. In summary, TME-related exosomes can be a potential target to reverse chemoresistance and a candidate biomarker of drug efficacy in HCC patients.

Background: DNA primase subunit 1 (PRIM1) has been reported as a novel oncogene in several cancer types. However, its roles in hepatocellular carcinoma (HCC) remain unclear. This study aimed to investigate underlying mechanisms of PRIM1 and identify it as a potential molecular target for HCC. Methods: Hub genes were screened between HCC tissues and normal liver tissues in 3 gene expression omnibus (GEO) datasets and the cancer genome atlas (TCGA). The expression features and prognostic value of one of the hub genes PRIM1 were analyzed by bioinformatic analyses and immunohistochemistry. Loss-of-function and gain-of-function studies were used to investigate the regulatory role of PRIM1 in HCC cells. Real-time (RT)-qPCR, western blotting, and ubiquitin immunoprecipitation assays were performed to explore the underlying mechanisms. The xenograft model was employed to detect the roles of PRIM1 in tumor growth in vivo. Finally, the 3D spheroid model was conducted to validate the role of PRIM1 in tumor growth and sorafenib resistance. Results: The hub genes of HCC were screened in multiple bioinformatic datasets. PRIM1, as one of the hub genes, was significantly overexpressed in HCC tissues in mRNA and protein levels. In addition, high expression of PRIM1 indicated poor prognosis of HCC patients in TCGA, ICGC, and Nantong cohorts. Overexpression of PRIM1 promoted the proliferation, migration/invasion, and sorafenib resistance of HCC cells, with the decrease in apoptosis and cell cycle arrest. Mechanically, PRIM1 facilitated epithelial-mesenchymal transition (EMT) process and the activity of PI3K/AKT/mTOR signaling of HCC cells. Additionally, PRIM1 could cause the ubiquitination and degradation of P53 by upregulating Ubiquitin Conjugating Enzyme E2 C (UBE2C). Furthermore, knockdown of PRIM1 significantly inhibited the growth of xenograft tumors and HCC cells-derived spheroids with enhanced sorafenib resistance. Conclusion: This study implies that PRIM1 may play a key role in the progression of HCC and may serve as a potential target for HCC treatment.