Tspan5 promotes epithelial-mesenchymal transition and tumour metastasis of hepatocellular carcinoma by activating Notch signalling.

Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide due to a high rate of tumour metastasis and disease recurrence. In physiological conditions, tetraspanins interact with specific partner proteins in tetraspanin-enriched microdomains and regulate their subcellular localization and function. However, the function of Tspan5 in pathological processes, particularly in cancer biology and its clinical significance, are still unclear. Here, we describe that a high expression of Tspan5 is significantly associated with some clinicopathological features including invasive length, vascular invasion, clinical stage and poor overall survival of HCC patients. Alterations of Tspan5 expression by lentivirus transductions in HCC cells demonstrated that Tspan5 promotes wound healing and cell migration in vitro and tumour metastasis of HCC cells in vivo. Mechanistic studies revealed that Tspan5 promoted cell migration and tumour metastasis by increasing the enzymatic maturation of ADAM10 and activating Notch signalling via the increase of the cleavage of the Notch1 receptor catalysed by the γ-secretase complex. Activation of Notch signalling by Tspan5 was shown further to enhance the epithelial-mesenchymal transition (EMT) and actin skeleton rearrangement of tumour cells. In clinical HCC samples, Tspan5 expression is strongly correlated with many key molecules acting in Notch signalling and EMT, highlighting the role of Tspan5 in the regulation of Notch signalling, EMT and tumour metastasis of HCC. Our findings provide new insights into the mechanism of tumour metastasis and disease progression of HCC and may facilitate the development of novel clinical intervention strategies against HCC.

Reduced expression of CENP-E contributes to the development of hepatocellular carcinoma and is associated with adverse clinical features.

Human kinesin centromere-associated protein E (CENP-E), one of spindle checkpoint proteins, has been identified as a tumor suppressor in several types of cancer, however, its role in hepatocarcinogenesis remains unknown. Here we investigated the role of CENP-E in human hepatocellular carcinoma (HCC) employing HCC cell lines (Hep3B, SMMC7721, and QGY7701), animal models, and patient's clinical samples and data. We demonstrated that down-regulation of CENP-E by CENP-E-silencing shRNAs significantly promoted HCC proliferation/growth both in vitro and in vivo. Further studies found that CENP-E suppressed the proliferation of HCC cells by halting cell cycle progression at the G1-S phase and accelerating cell apoptosis. Analyses of HCC patient samples and clinical data revealed that CENP-E was significantly down-regulated in HCC tissues and low CENP-E expression was significantly associated with patient's adverse clinicopathological features: poor prognosis, advanced TNM stage, metastasis, and larger tumor size. Multivariate analysis indicated that CENP-E was an independent prognostic factor predicting outcomes of advanced HCC patients. Our data suggest that loss of CENP-E contributes to HCC development and is strongly associated with adverse HCC clinical pathology. Thus, CENP-E could be a novel target for new treatments and a useful prognostic biomarker for HCC patients.

Tspan5 is an independent favourable prognostic factor and suppresses tumour growth in gastric cancer.

Tetraspanins are believed to interact with specific partner proteins forming tetraspanin-enriched microdomains and regulate some aspects of partner protein functions. However, the role of Tspan5 during pathological processes, particularly in cancer biology, remains unknown. Here we report that Tspan5 is significantly downregulated in gastric cancer (GC) and closely associated with clinicopathological features including tumour size and TNM stage. The expression of Tspan5 is inversely correlated with patient overall survival and is an independent prognostic factor in GC. Upregulation of Tspan5 in tumour cells results in inhibition of cell proliferation and colony formation in vitro and suppression of xenograft growth of GC by reducing tumour cell proliferation in vivo. Thus, Tspan5 functions as a tumour suppressor in stomach to control the tumour growth. Mechanistically, Tspan5 inhibits the cell cycle transition from G1-S phase by increasing the expression of p27 and p15 and decreasing the expression of cyclin D1, CDK4, pRB and E2F1. The correlation of Tspan5 expression with the expression of p27, p15, cyclin D1, CDK4, pRB and E2F1 in vivo are also revealed in xenografted tumours. Reconstitution of either cyclin D1 or CDK4 in Tspan5-overexpressing GC cells rescues the inhibitory phenotype produced by Tspan5, suggesting that cyclin D1/CDK4 play a dominant role in mediating the suppression of tumour growth by Tspan5 in GC. Our results suggest that Tspan5 may serve as a prognostic biomarker for predicting outcome of GC patients and provide new insights into the pathogenesis of GC and rational for the development of clinical intervention strategies against GC.