PDSS2-Del2, a new variant of PDSS2, promotes tumor cell metastasis and angiogenesis in hepatocellular carcinoma via activating NF-κB

Autor: Daqin Suo, Lili Liang, Zhi Tang, Yunfei Yuan, Lei Li, Yan Li, Jiangchao Li, Xin Yuan Guan, Tingting Zeng
Rok vydání: 2020
Předmět:
0301 basic medicine
Male
Cancer Research
Angiogenesis
Metastasis
chemistry.chemical_compound
angiogenesis
0302 clinical medicine
Fumarates
Cell Movement
Neoplasm Metastasis
Wnt Signaling Pathway
Research Articles
Mice
Inbred BALB C
Tissue microarray
dimethyl fumarate
Dimethyl fumarate
Neovascularization
Pathologic
nuclear factor‐κB
Liver Neoplasms
Wnt signaling pathway
NF-kappa B
General Medicine
hepatocellular carcinoma
Middle Aged
Oncology
030220 oncology & carcinogenesis
Hepatocellular carcinoma
Molecular Medicine
Female
Research Article
Adult
Carcinoma
Hepatocellular
Epithelial-Mesenchymal Transition
Mice
Nude
Context (language use)
03 medical and health sciences
Young Adult
In vivo
Cell Line
Tumor
Genetics
medicine
Animals
Humans
metastasis
neoplasms
Aged
Alkyl and Aryl Transferases
business.industry
PDSS2‐Del2
medicine.disease
Survival Analysis
digestive system diseases
030104 developmental biology
chemistry
Dietary Supplements
Microvessels
Cancer research
business
Zdroj: Molecular Oncology
ISSN: 1878-0261
Popis: Unlike full‐length PDSS2, which has a tumor‐suppressive function, PDSS2‐Del2 promoted HCC metastasis and angiogenesis. Positive staining for PDSS2‐Del2 predicted a worse overall survival in patients with HCC. Elevated PDSS2‐Del2 expression in HCC tumor cells decreased fumarate levels and activated the canonical NF‐κB pathway. Dimethyl fumarate (DMF) might be a potential treatment for metastasis of patients with HCC.
Hepatocellular carcinoma (HCC) is among the leading causes of cancer‐related mortality worldwide. Our previous study identified a novel alternative splicing variant of prenyl diphosphate synthase subunit 2 (PDSS2) in HCC characterized by a deletion of exon 2, named PDSS2‐Del2, which is devoid of the tumor‐suppressive function of full‐length PDSS2 (PDSS2‐FL). To better understand the clinical significance of PDSS2‐Del2, we performed a BaseScope™ assay on an HCC tissue microarray and found that positive staining for PDSS2‐Del2 predicted a worse overall survival in patients with HCC (P = 0.02). PDSS2‐Del2 levels correlated significantly with microvessel counts in HCC tumor tissues. Importantly, PDSS2‐Del2 overexpression functionally promoted HCC metastasis, as demonstrated by in vitro and in vivo migration assays. In vivo assays also demonstrated that PDSS2‐Del2 increased angiogenesis in xenografts. Furthermore, we discovered that elevated PDSS2‐Del2 expression in HCC tumor cells decreased fumarate levels and activated the canonical nuclear factor‐κB pathway. The epithelial‐to‐mesenchymal transition (EMT) and WNT/β‐catenin signaling pathways were also activated by overexpression. Dimethyl fumarate (DMF), a fumaric acid ester, effectively reduced the metastasis induced by PDSS2‐Del2 as observed with in vivo spleen‐liver metastasis animal experiments. DMF is a prescribed oral therapy for multiple sclerosis and it might be a potential treatment for metastasis of patients with HCC. Early clinical trials are needed to validate its potential in this context.
Databáze: OpenAIRE
Externí odkaz: