Dataset Information

Downregulation of serum RAB27B confers improved prognosis and is associated with hepatocellular carcinoma progression through PI3K-AKT-P21 signaling.

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.

SUBMITTER: Yang X

PROVIDER: S-EPMC5617411 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Downregulation of serum RAB27B confers improved prognosis and is associated with hepatocellular carcinoma progression through PI3K-AKT-P21 signaling.

Yang Xue X Ye Xieqiong X Sun Le L Gao Fangyuan F Li Yuxin Y Ji Xiaomin X Wang Xuejiang X Feng Ying Y Wang Xianbo X

Oncotarget 20170519 37

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 Barcelon ...[more]

PMID: 28977851

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Project description:BackgroundMitochondrial dysfunction and metabolic reprogramming can lead to the development and progression of hepatocellular carcinoma (HCC). Ferredoxin 1 (FDX1) is a small mitochondrial protein and recent studies have shown that FDX1 plays an important role in tumor cuproptosis, but its role in HCC is still elusive. In this study, we aim to investigate the expression and novel functions of FDX1 in HCC.MethodsFDX1 expression was first analyzed in publicly available datasets and verified by immunohistochemistry, qRT-PCR and Western blot. In vitro and in vivo experiments were applied to explore the functions of FDX1. Non-targeted metabolomics and RNA-sequencing were used to determine molecular mechanism. mRFP-GFP-LC3 lentivirus transfection, Mito-Tracker Red and Lyso-Tracker Green staining, transmission electron microscopy, flow cytometry, JC-1 staining, etc. were used to analyze mitophagy or ROS levels. Hydrodynamic tail vein injection (HTVi) and patient-derived organoid (PDO) models were used to analyze effect of FDX1 overexpression.ResultsFDX1 expression is significantly downregulated in HCC tissues. FDX1 downregulation promotes HCC cell proliferation, invasion in vitro and growth, metastasis in vivo. In addition, FDX1 affects metabolism of HCC cells and is associated with autophagy. We then confirmed that FDX1 deficiency increases ROS levels, activates mitophagy and the PI3K/AKT signaling pathway in HCC cells. Interestingly, scavenging ROS attenuates the tumor-promoting role and mitophagy of FDX1 downregulation. The results of HTVi and PDO models both find that FDX1 elevation significantly inhibits HCC progression. Moreover, low FDX1 expression is associated with shorter survival and is an independent risk factor for prognosis in HCC patients.ConclusionsOur research had investigated novel functions of FDX1 in HCC. Downregulation of FDX1 contributes to metabolic reprogramming and leads to ROS-mediated activation of mitophagy and the PI3K/AKT signaling pathway. FDX1 is a potential prognostic biomarker and increasing FDX1 expression may be a potential therapeutic approach to inhibit HCC progression.

Project description:Background: LncRNA is a key factor influencing tumor development. The present study aimed to investigate the effect of a novel lncRNA on the progression of hepatocellular carcinoma (HCC). Methods: A candidate lncRNA in The Cancer Genome Atlas database was identified using limma and survival R packages. The effect of lncRNA AC099850.3 on cell proliferation, apoptosis, migration, and invasion, as well as its association with immune cells in HCC were investigated. Furthermore, the functional mechanisms of lncRNA AC099850.3 in HCC were elucidated. Results: The aberrant expression of lncRNA AC099850.3 was identified in tumor tissues and its prognostic relevance in HCC was determined. The results revealed that AC099850.3 was highly expressed in HCC tissues and cell lines, and it predicted poor prognosis in patients with HCC. Furthermore, knockdown of AC099850.3 significantly suppressed the proliferation and metastatic potential of HCC cells, and promoted cell apoptosis in HCC cells. The results of gene set enrichment analysis revealed that the PI3K/AKT pathway was associated with the biological function of AC099850.3, which was further validated by western blotting. PRR11 was identified as the target gene of AC099850.3 and we established that AC099850.3 acted as an oncogene in the PRR11/PI3K/AKT axis. Immune cell infiltration analyses results revealed that AC099850.3 was positively correlated with T follicular helper cells, M0 macrophages, CD4+ memory T cells, and memory B cells. Conversely, AC099850.3 was negatively correlated with M2 macrophages, monocytes, natural killer cells, and CD8+ T cells, which could be responsible for its oncogenic effect. Of note, a significantly positive correlation was observed between AC099850.3 and key immune checkpoint molecules (PD-1, PD-L1, PD-L2, and CTLA4) in the present study, making AC099850.3 a potential immune therapeutic target for HCC. Conclusion: AC099850.3 can promote malignant biological behavior of HCC cells, and could be a potential biomarker and therapeutic target for HCC.

Dataset Information

Downregulation of serum RAB27B confers improved prognosis and is associated with hepatocellular carcinoma progression through PI3K-AKT-P21 signaling.

Publications

Downregulation of serum RAB27B confers improved prognosis and is associated with hepatocellular carcinoma progression through PI3K-AKT-P21 signaling.

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