Abstract
Postsurgical recurrence within 2 years is the major cause of poor survival of hepatocellular carcinoma (HCC) patients. However, the molecular mechanism underlying HCC recurrence remains unclear. Here, we distinguish the function and mechanism of Sec62 in promoting HCC recurrence. The correlation between Sec62 and early recurrence was demonstrated in 60 HCC samples from a prospective study. HCC cells with Sec62 knockdown (Sec62KD) or overexpression (Sec62OE) were used to determine the potential of Sec62 in cell migration in vitro. Microarray analysis comparing Sec62KD or Sec62OE to their control counterparts was used to explore the mechanisms of Sec62-induced recurrence. A luciferase-labelled orthotopic nude mouse model of HCC with Sec62KD or Sec62OE was used to validate the potential of Sec62 in early HCC recurrence in vivo. We found that high expression of Sec62 was positively correlated with surgical recurrence in clinical HCC samples. Multivariate analysis revealed that Sec62 was an independent prognostic factor for early recurrence in postoperative HCC patients. Moreover, Sec62 promoted migration and invasion of HCC cells in vitro and postsurgical recurrence in vivo. Mechanically, integrinα/CAV1 signalling was identified as one of the targets of Sec62 in cell movement. Overexpression of integrin α partially rescued the Sec62 knockdown-induced inhibition of cell migration. Sec62 is a potentially prognostic factor for early recurrence in postoperative HCC patients and promotes HCC metastasis through integrinα/CAV1 signalling. Sec62 might be an attractive drug target for combating HCC postsurgical recurrence.
Highlights
Hepatocellular carcinoma (HCC) was the fourth leading cause of cancer death worldwide in 2018, with ~841,000 new cases and 782,000 deaths annually[1]
The area under the ROC curve (AUC) was 0.89 (Fig. 1Sb). These results suggest that Sec[62] is closely correlated with early recurrence and may be a potential predictor for postsurgical recurrence of HCC
Up-regulation of Sec[62] expression increased the migration and invasion of 97L cells. These results suggest that Sec[62] may promote postsurgical recurrence of HCC by increasing HCC cell migration and invasion
Summary
Hepatocellular carcinoma (HCC) was the fourth leading cause of cancer death worldwide in 2018, with ~841,000 new cases and 782,000 deaths annually[1]. The major risk factors of HCC vary from region to region. The mortality rates of HCC have increased in northern and central Europe and the USA, where the leading risk factors include alcohol consumption, increased overweight/obesity, and diabetes[3]. Liver transplantation or local ablation are recommended for patients with very early stage tumours (Barcelona Clinic Liver Cancer [BCLC] 0/A). For patients with well-preserved hepatic function, surgical resection provides a better clinical outcome than local ablation[5,6]. Metastasis is the major reason for the high recurrence and poor survival of
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