Background: The high metastasis rate is one of the main reasons for the poor prognosis of patients with hepatocellular carcinoma (HCC). Coagulation factor Xa (FXa) and its receptor proteinase-activated receptor-2 (PAR-2) proven to promote tumor metastasis in other forms of cancer. Here, we explore the role and mechanism of FXa in the regulation of resistance of anoikis and immune escape of HCC. Methods: In vitro and in vivo experiments were conducted to explore the role of FXa in HCC metastasis and its potential mechanism. The effects of FXa inhibitor rivaroxaban on HCC immunotherapy were evaluated using intrahepatic metastasis animal models and clinical trial (No. ChiCTR20000040540). We investigated the potential of FXa inhibition as a treatment for HCC. Results: FXa was highly expressed in HCC and promoted metastasis by activating PAR-2. Mechanistically, FXa-activated PAR-2 endows HCC cells with the ability of anoikis resistance to survive in the circulating blood by inhibiting the extrinsic apoptosis pathway. Furthermore, suspension stimulation-induced phosphorylation of STAT2, which promotes programmed death-ligand 1 (PD-L1) transcription and inhibits the antitumor effects of immune cells by inhibiting the infiltration of CD8⁺T cells in tumors and the levels of secreted cytokines. In vivo inhibition of FXa with rivaroxaban reduced HCC metastasis by decreasing PD-L1 expression and exhausting tumor-infiltrating lymphocytes. Notably, the combination of rivaroxaban and anti-programmed death-1 monoclonal antibody (anti-PD-1) programmed Death-1 monoclonal antibody (anti-PD-1) induced synergistic antitumor effects in animal models. Most importantly, rivaroxaban improved the objective response rate of patients with HCC to immune checkpoint inhibitors and prolonged overall survival time. Conclusions: FXa-activated PAR-2 promotes anoikis resistance and immune escape in HCC, suggesting the potential for combining coagulation inhibitors and PD-1/PD-L1 immune checkpoint blockade to enhance the therapeutic efficacy of HCC.

Hepatocellular carcinoma (HCC) is the most common type of primary liver malignancy, with increased mortality and morbidity. Accumulating evidence suggested that 40S ribosomal protein S24 (RPS24) is related to malignant outcomes and progression. However, the role of RPS24 remains unclear in HCC. The mRNA and protein expression pattern of RPS24 in HCC was explored and confirmed based on the bioinformatics analysis and histological examination. The correlation between RPS24 expression and clinicopathological features, diagnostic value, prognosis, methylation status, and survival were evaluated. Then, we divided the HCC cohort into two groups based on the expression of RPS24, and performed the functional enrichment and immune cells infiltration analysis of RPS24. Furthermore, in vivo and in vitro experiments were performed to investigate the effect of RPS24 on HCC cells. RPS24 was observed to be elevated in HCC samples. RPS24 overexpression or RPS24 promoter methylation contributed to an unfavorable prognosis for HCC patients. The genes in the high RPS24 expression group were mainly enriched in DNA replication, cell cycle E2F targets, and the G2M checkpoint pathway. Moreover, the expression level of RPS24 was significantly related to immune infiltration and immunotherapy response. Our experiments also demonstrated that RPS24 knockdown suppressed the growth of HCC cells and tumor proliferation of the xenograft model. Therefore, RPS24 can be a potential adverse biomarker of HCC prognosis acting through facilitating cell proliferation and the formation of an immunosuppressive microenvironment in HCC. Targeting RPS24 may offer a promising therapeutic option for HCC management.

Background: Understanding the metastatic risks and patterns of colon cancer is crucial for patient evaluation and decision-making. However, high-quality evidence on colon cancer metastases is lacking. This study aims to conduct a systematic review and meta-analysis to determine the risk of site-specific metastasis and provide a complete profiling of distant metastasis in colon cancer. Methods: This review will include studies reporting the proportion of different-site metastases among colon cancer patients. Clinical trials, follow-up studies, and cross-sectional surveys with English publications are eligible for inclusion. We will search Medline, Embase, Web of Science, and the Cochrane Library from inception to June 2023. Two reviewers will independently screen the title/abstract and full texts of identified records according to the eligibility criteria. Data from eligible studies will be extracted and used for meta-analysis. Meta-analyses will be conducted to estimate the overall proportion of site-specific metastasis. During meta-analyses, two proportions will be analyzed, i.e., the incidence of metastasis and component proportion. We will select the appropriate tools to assess the risk of biases based on the study design of included studies. Results: This study is still in preparation for launch. Once all analyses are complete, the results will be submitted for publication in a peer-reviewed journal. Conclusion: This review will provide a clear and systematic metastatic pattern of colon cancer and evidence-based recommendations for the management of distant metastasis.