Previous clinical studies have found that the levels of tumor-infiltrating lymphocytes (TILs) significantly correlated with prognosis in hepatocellular carcinoma (HCC). However, these conclusions and data remain controversial. We performed a systematic review and meta-analysis to assess the prognostic value and clinical utilization of TILs in patients with HCC. A total of 23 relevant studies of 3173 patients were included into our meta-analysis. The results demonstrated that high levels of CD8+ and CD3+ TILs had a better prognostic value on overall survival (OS), with HRs of 0.71 (P = 0.04) and 0.63 (P = 0.03), respectively, compared to low levels, as did high levels of CD8+, CD3+ and CD4+ TILs on disease/recurrence-free survival (DFS/RFS), with HRs of 0.66 (P = 0.01), 0.60 (P = 0.01) and 0.79 (P = 0.04), respectively. In contrast, high levels of FoxP3+ TILs had a worse prognostic value on OS and DFS/RFS, with HRs of 2.06 (P < 0.00001) and 1.77 (P < 0.00001), respectively. The FoxP3+/CD4+ and FoxP3+/CD8+ ratios negatively correlated with OS and DFS/RFS. These findings suggest that TILs may serve as a prognostic biomarker in HCC. However, further research should be performed to clarify the clinical value of TILs in HCC.

These results demonstrate that aPKC-ι promotes EMT and induces immunosuppression through the aPKC-ι/P-Sp1/Snail signaling pathway and may be a potential therapeutic target for CCA. (Hepatology 2017;66:1165-1182).

Cholangiocarcinoma (CCA) invasion and metastasis are the primary causes of poor survival rates in patients. The epithelial-mesenchymal transition (EMT) is a crucial step in cancer invasion and metastasis. However, it is still unclear of the molecular mechanism. In this study, the expression of 14-3-3ζ and atypical protein kinase C-ι (aPKC-ι) was further detected in CCA tissues and cell lines. Meanwhile, we established the EMT model of CCA cells and investigated 14-3-3ζ and aPKC-ι co-regulatory effect on the EMT in vitro and in vivo. Further, we identified the downstream molecular glycogen synthase kinase 3 beta (GSK-3β)/Snail signalling pathway that contribute to regulating the EMT. Our data showed that the expression of 14-3-3ζ and aPKC-ι was synergistically increased in CCA tissues compared with adjacent noncancerous tissues and was intimately associated with differentiation and the tumour-node-metastasis (TNM) stage. Multivariate Cox regression analysis indicated that high 14-3-3ζ and aPKC-ι expression separately predicted a poor prognosis and were independent prognostic indicators in patients with CCA. The CO-IP experiment confirmed that the mutual binding relationship between 14-3-3ζ and aPKC-ι. Small interfering RNAs and siRNA rescue experiment demonstrated that 14-3-3ζ and aPKC-ι regulated each other. In addition, 14-3-3ζ and aPKC-ι pretreatment by si-RNA inhibit the phosphorylated GSK-3β and Snail expression during EMT. Meanwhile, silence of 14-3-3ζ or aPKC-ι suppressed CCA cells migration, metastasis and proliferation in vitro and in vivo. Our study demonstrates that 14-3-3ζ and aPKC-ι synergistically facilitate EMT of CCA via GSK-3β/Snail signalling pathway, and may be potential therapeutic target for CCA.