Abstract
Previous study revealed that elevated expression of RAB27B in tissues is correlated with hepatocellular carcinoma (HCC) progression; however, the mechanisms involved in promoting HCC development are still unclear. Moreover, HCC tissues are not readily obtained during routine diagnosis. Therefore, to further explore its potential value in early diagnosis, we examined RAB27B expression in patient sera. First, the correlation between serum RAB27B expression and survival, as well as TNM and Barcelona Clinic Liver Cancer stages, were evaluated in patients with HCC. Second, lentiviral vector plasmids carrying interference sequences and plasmids harboring the complete open reading frame of RAB27B were designed to knockdown or overexpress RAB27B in BEL7402 or HuH-7 cells to determine its biological function. Compared with healthy controls and patients with chronic hepatitis B infection, serum RAB27B was significantly increased in patients with HCC. After down-regulating expression of RAB27B, the proliferation of BEL7402 cells was remarkably inhibited both in vitro and in vivo. Additionally, activation of the PI3K/AKT pathway was significantly diminished. Moreover, cell cycle progression of the knockdown cells was notably arrested in the G1/S phase, and upregulation of p21 contributed to this effect. Restoration experiments to recover RAB27B expression revealed opposing results. These findings indicated RAB27B might regulate cell cycle through the PI3K/AKT/p21 pathway by releasing cytokines via exocytosis, thereby modulating the proliferation of HCC cells. RAB27B could potentially be a valuable serum biomarker for the early diagnosis of, and a therapeutic target in, HCC.
Highlights
Primary liver cancer (PLC) is the sixth-most common malignant cancer and the third-ranked cause of cancer-related deaths, with a high rate of malignancy and mortality worldwide [1]
Univariate analysis showed that RAB27B, ALT, AST, TBil, ALB, ALP, GGT, NLR, AFP, tumor number ≥ 3, tumor size ≥ 5 cm, hepatitis B virus (HBV) DNA ≥ 500 IU/ml, ChildPugh score, hepatic encephalopathy, ascites, lymph node metastasis, BCLC stages and portal vein involvement were associated with decreased overall survival in patients with hepatocellular carcinoma (HCC) (p < 0.05, Table 1)
In estrogen receptor (ER)-positive breast cancer cell lines, RAB27B was found to promote cell growth, invasion, and metastasis by secreting pro-invasive signaling molecules, and its high expression was associated with poor prognosis [19]
Summary
Primary liver cancer (PLC) is the sixth-most common malignant cancer and the third-ranked cause of cancer-related deaths, with a high rate of malignancy and mortality worldwide [1]. The occurrence and progression of HCC is closely related to dysregulation of the cell cycle, which can lead to excessive and uncontrolled cell proliferation. The cell cycle is regulated by the activity of cyclin-dependent kinases (CDKs) and cyclin-dependent kinase inhibitors (CDKIs), including p21 [5, 6]. The activity of p21 is governed by mitotic cascade signaling and cell damage responses, and studies have shown that its function is related to its subcellular location [7,8,9,10]. Studies have revealed that the activation of AKT enables phosphorylation of two residues of p21, T145 and T146. Phosphorylation at T145 induces the translocation of p21 from the nucleus to the cytoplasm, where it exerts its pro-cell growth and anti-apoptotic effects [11,12,13]
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