LukS-PV inhibits hepatocellular carcinoma cells migration by downregulating HDAC6 expression.

BACKGROUND: Hepatocellular carcinoma (HCC) is a clinically common malignant tumor worldwide. LukS-PV is the S component of Panton-Valentine leukocidin secreted by Staphylococcus aureus, which has shown anti-cancer activity. Based on previous findings, this study investigated the effects of LukS-PV on HCC migration and the potential molecular mechanisms involving acetylation pathways. METHODS: After treating HCC cells with different concentrations of LukS-PV, we used scratch assays to determine the mobility of the cancer cells. Western blots were used to determine the expression levels of migration-related proteins. Quantitative proteomic sequencing was used to evaluate proteomic changes in target proteins. Immunoprecipitation and liquid chromatography coupled with tandem mass spectrometry analyses were used to validate the binding of related target proteins. RESULTS: LukS-PV inhibited HCC cell migration in a concentration-dependent manner. In addition, LukS-PV attenuated the expression of histone deacetylase (HDAC)6, which is highly expressed in HCC cells. Further studies showed that LukS-PV increased the acetylation level of α-tubulin by down-regulating HDAC6, which resulted in the inhibition of HCC cell migration. CONCLUSION: Taken together, our data revealed a vital role of LukS-PV in suppressing HCC cell migration by down-regulating HDAC6 and increasing the acetylation level of α-tubulin.

LukS-PV inhibits the proliferation of hepatocellular carcinoma cells by maintaining FOXO3 stability via the PI3K/AKT signaling pathway.

Hepatocellular carcinoma(HCC) is one of the common malignant tumors. LukS-PV is the S component of Panton-Valetine leukocidin(PVL) secreted by Staphylococcus aureus. Forkhead box O3 (FOXO3) is a member of the FOXO subfamily of transcription factors that acts as a tumor suppressor. In this study, we investigated the role of LukS-PV on the proliferation of HCC and explored possible mechanisms. We treated HCC cells with various concentrations of LukS-PV and evaluated the effect of LukS-PV on cell viability using the cell counting kit-8 and colony formation assays. Real-time PCR and western blot assays were used to analyze mRNA and protein expression levels, respectively. Immunofluorescence staining was performed to examine the intracellular localization of FOXO3. The expression of FOXO3 and its downstream target genes were analyzed by immunohistochemical staining. The protein synthesis inhibitor cycloheximide and the proteosome inhibitor MG132 were used to explore the potential mechanisms by which LukS-PV regulated FOXO3. We demonstrated that LukS-PV inhibited the proliferation of HCC cells in a concentration dependent manner. LukS-PV upregulated FOXO3 expression both in vitro and in vivo. Moreover, LukS-PV facilitated the entry of FOXO3 into the nucleus and, subsequently, regulated the transcription of downstream target genes. In addition, we discovered that LukS-PV decreased the expression of phosphorylated FOXO3 through the PI3K/AKT signaling pathway and maintained FOXO3 protein stability via the ubiquitin-proteasome pathway. Taken together, our data indicated that LukS-PV exert anticancer activities through FOXO3. LukS-PV may be a promising candidate for HCC treatment.

Clinicopathological features and prognostic significance of C5aR in human solid tumors: a Meta-analysis.

BACKGROUND: C5aR has been extensively studied in recent years as an essential component of the complement system. However, the role of C5aR in tumors has not been sufficiently investigated and summarized. The aim of this meta-analysis was to investigate the prognostic value of C5aR in solid tumors as well as the correlation between C5aR and clinicopathological features. METHODS: Relevant study collection was performed in PubMed, Embase, Web of Science, BIOSIS Previews, Cochrane Library until July 10, 2021. Pooled hazard ratios (HRs), odds ratios (ORs), and 95% confidence intervals (CIs) were calculated. Sensitivity analyses were performed to assess the robustness of this study, while publication bias was tested by Begg's and Egger's tests. RESULTS: A total of 11 studies involving 1577 patients were included in the study. Our results suggest that the high-level C5aR expression in tumor tissue predicted unsatisfactory overall survival (OS) (HR = 1.92, 95% CI:1.47-2.50, P < 0.001) and recurrence-free survival (RFS) (HR = 2.19, 95% CI:1.47-3.27, P < 0.001). Besides, a higher level of C5aR expression was associated with larger tumor size (OR = 1.58, 95% CI: 1.18-2.10, P = 0.002) and the occurrence of metastases in lymph nodes (OR = 1.99, 95% CI: 1.46-2.72, P<0.001), whereas it was independent of tumor stage, vascular invasion and tumor differentiation. CONCLUSION: In conclusion, C5aR may be a potential biomarker for evaluating tumor prognosis and treatment.

Erratum: LukS-PV Inhibits Hepatocellular Carcinoma Progression by Downregulating HDAC2 Expression.

[This corrects the article DOI: 10.1016/j.omto.2020.05.006.].

LukS-PV Inhibits Hepatocellular Carcinoma Cells Migration via the TNNC1/PI3K/AKT Axis.

PURPOSE: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. LukS-PV is the S component of Panton-Valentine leucocidin (PVL), a toxin secreted by Staphylococcus aureus. We aimed to investigate the role of LukS-PV in HCC cell migration and the specific molecular mechanism involved. METHODS: We used scratch assays to detect the mobility of liver cancer cells treated with LukS-PV. Quantitative real-time PCR and Western blot analysis were performed to detect the expression levels of related genes. RNA sequencing and quantitative proteomics sequencing were used to assess the transcriptional and proteomic alterations of target genes. RNA sequencing and Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) pathway analyses revealed the downstream signaling pathway targets of LukS-PV. RESULTS: Our results demonstrated that LukS-PV could inhibit HCC cell migration in a concentration-dependent manner. LukS-PV could also downregulate the expression of TNNC1, which was highly expressed in HCC cells. Additionally, the study showed that LukS-PV inhibited HCC cell migration by downregulating TNNC1. Further studies showed that LukS-PV inhibited the phosphorylation of PI3K/AKT pathway by targeting TNNC1, thereby inhibiting HCC cell migration. CONCLUSION: Our study demonstrated that LukS-PV has an inhibitory role in the migration of liver cancer cells through the TNNC1/PI3K/AKT axis.

LukS-PV Inhibits Hepatocellular Carcinoma Progression by Downregulating HDAC2 Expression.

Hepatocellular carcinoma (HCC) is a common malignant tumor. LukS-PV is the S component of Panton-Valetine leukocidin (PVL), which is secreted by Staphylococcus aureus. This study investigated the effects of LukS-PV on the proliferation, apoptosis, and cell-cycle progression of HCC cells and the mechanisms of its activity. The HCC cells were treated with different LukS-PV concentrations in vitro. Cell Counting Kit-8 and 5-Ethynyl-2'-deoxyuridine (EdU) assays were used to study cell proliferation. Flow cytometry was used to measure apoptosis and cell-cycle progression. Quantitative reverse transcriptase PCR and western blot assays were used to determine mRNA and protein expression levels. Xenograft experiments were performed to determine the in vivo antitumor effect of LukS-PV. Immunostaining was performed to analyze Ki-67 and HDAC2 (histone deacetylase 2) expression. Our results showed that LukS-PV inhibited cell proliferation and induced apoptosis in a concentration-dependent manner in HCC cell lines. LukS-PV also can induce cell-cycle arrest. Moreover, we discovered that LukS-PV attenuated HDAC2 expression and upregulated PTEN; phosphorylated AKT was also reduced. Further studies demonstrated that LukS-PV treatment significantly reduced tumor growth in nude mice and suppressed Ki-67 and HDAC2 levels. Our data revealed a vital role of LukS-PV in suppressing HCC progression by downregulating HDAC2 and upregulating PTEN.

LukS-PV induces cell cycle arrest and apoptosis through p38/ERK MAPK signaling pathway in NSCLC cells.

Non-small-cell lung cancer (NSCLC) accounts for nearly 85% of lung cancer cases. LukS-PV, one of the two components of Panton-Valentine leucocidin (PVL), is produced by Staphylococcus aureus. The present study showed that LukS-PV can induce apoptosis in human acute myeloid leukemia (AML) lines (THP-1 and HL-60). However, the role of LukS-PV in NSCLC is unclear. In this study, we treated NSCLC cell lines A549 and H460 and a normal lung cell line, 16HBE, with LukS-PV and investigated the biological roles of LukS-PV in NSCLC. Cells were treated with varying concentrations of LukS-PV and cell viability was evaluated by CCK8 and EdU assay. Flow cytometry was used to detect cell apoptosis and analyze the cell cycle, and the expression of apoptosis and cell cycle-associated proteins and genes were identified by western blotting analysis and qRT-polymerase chain reaction, respectively. We found that LukS-PV inhibited the proliferation of NSCLC cells but had little cytotoxicity in normal lung cells. LukS-PV induced NSCLC cell apoptosis and increased the BAX/BCL-2 ratio, triggering S-phase arrest in A549 and H460 cells while increasing P21 expression and decreasing CDK2, cyclin D1, and cyclin A2 expression. We also observed increased P-p38 and P-ERK in NSCLC cells treated with LukS-PV. Treatment of NSCLC with LukS-PV combined with p38 and ERK inhibitors reversed the pro-apoptotic and pro-cell cycle arrest effects of LukS-PV. Overall, these findings indicate that LukS-PV has anti-tumor effects in NSCLC and may contribute to the development of anti-cancer agents.