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EZH2, a histone methyltransferase, has been shown to involve in cancer development and progression via epigenetic regulation of tumor suppressor microRNAs, whereas BMI1, a driver of hepatocellular carcinoma (HCC), is a downstream target of these microRNAs. However, it remains unclear whether EZH2 can epigenetically regulate microRNA expression to modulate BMI1-dependent hepatocarcinogenesis. Here, we established that high EZH2 expression correlated with enhanced tumor size, elevated metastasis, increased relapse, and poor prognosis in HCC patients. Further clinical studies revealed that EZH2 overexpression was positively correlated to its gene copy number gain/amplification in HCC. Mechanistically, EZH2 epigenetically suppressed miR-200c expression both in vitro and in vivo, and more importantly, miR-200c post-transcriptionally regulated BMI1 expression by binding to the 3′-UTR region of its mRNA. Furthermore, miR-200c overexpression inhibits the growth of HCC cells in vivo. Silencing miR-200c rescued the tumorigenicity of EZH2-depleted HCC cells, whereas knocking down BMI1 reduced the promoting effect of miR-200c depletion on HCC cell migration. Finally, combination treatment of EZH2 and BMI1 inhibitors further inhibited the viability of HCC cells compared with the cells treated with EZH2 or BMI1 inhibitor alone. Our findings demonstrated that alteration of EZH2 gene copy number status induced BMI1-mediated hepatocarcinogenesis via epigenetically silencing miR-200c, providing novel therapeutic targets for HCC treatment.

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Background and AimsRecently, the pre-treatment platelet-lymphocyte ratio (PLR), which is based on blood parameters, was accepted as a prognostic factor for patients with various cancers. Numerous studies have investigated the prognostic role of the PLR in pancreatic cancer; however, it remains unclear. Therefore, we conducted this meta-analysis to evaluate the relationship between the pre-treatment PLR and overall survival (OS) in pancreatic cancer.Materials and MethodsWe performed a systematic literature search of the PubMed, Embase and Web of Science databases for relevant studies that explored the prognostic role of the pre-treatment PLR in pancreatic cancer. The hazard ratios (HRs) and 95% confidence intervals (CIs) related to OS were pooled using a random effects model.ResultsFourteen retrospective cohort studies involving 2,260 patients were included in this meta-analysis. Compared with low PLR, high PLR was a predictor of shorter OS (HR = 1.24, 95% CI: 1.10–1.39, I2 = 74%).ConclusionsIn this meta-analysis, high pre-treatment PLR was a bio-predictor of short OS in patients with pancreatic cancer, suggesting that PLR could be used to predict prognosis of patients with pancreatic cancer before treatment. However, additional well-designed and large-scale studies are necessary.

Ectopic lymphoid structures termed tertiary lymphoid structures (TLSs) have an immunomodulatory function and positively affect prognosis in certain cancers. However, their clinical relevance and prognostic utility in perihilar cholangiocarcinoma (pCCA) are unknown. Therefore, determining the involvement and prognostic utility of TLSs in pCCA is the aim of this study. Ninety-three patients with surgically resected pCCA were included retrospectively. Hematoxylin and eosin and immunohistochemical staining identified and classified the TLSs, and multiplex immunofluorescence determined the TLS composition in the pCCA sample. The correlations between clinical features and TLSs were analyzed using either Fisher’s exact test or the Chi-squared test. Recurrence-free survival (RFS) and overall survival (OS) correlations with TLSs were analyzed using Cox regression and Kaplan–Meier analyses. We identified TLSs in 86% of patients with pCCA, including lymphoid aggregates (6.45%), primary (13.98%) and secondary follicles (65.59%). Patients with intra-tumoral secondary follicle-like TLSs (S-TLSs) had better OS (p = 0.003) and RFS (p = 0.0313). The multivariate analysis identified the presence of S-TLSs as a good independent prognostic indicator for OS but not for RFS. Interestingly, the presence of S-TLS only indicated better 5-year OS in 54 patients without lymph node metastasis (LNM−, p = 0.0232) but not in the 39 patients with lymph node metastasis (LNM+, p = 0.1244). Intra-tumoral S-TLSs predicted longer OS in patients with surgically resected pCCA, suggesting intra-tumoral S-TLSs’ contribution to effective antitumor immunity and that S-TLSs hold promise for diagnostic and therapeutic development in pCCA.