Cathepsin C Interacts with TNF-α/p38 MAPK Signaling Pathway to Promote Proliferation and Metastasis in Hepatocellular Carcinoma

Autor: Xiao Yue, Guo-Pei Zhang, Shao-Qiang Li
Rok vydání: 2020
Předmět:
Adult
0301 basic medicine
Cancer Research
Carcinoma
Hepatocellular
Hepatocellular carcinoma
p38 Mitogen-Activated Protein Kinases
Cathepsin C
Metastasis
Mice
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
Cell Movement
Cell Line
Tumor
medicine
Animals
Humans
Neoplasm Metastasis
Cell proliferation
Aged
Neoplasm Staging
Proportional Hazards Models
Ralimetinib
Tissue microarray
Tumor Necrosis Factor-alpha
Cell growth
business.industry
Liver Neoplasms
Cell migration
Middle Aged
Prognosis
medicine.disease
digestive system diseases
Disease Models
Animal
030104 developmental biology
Oncology
030220 oncology & carcinogenesis
Cancer research
Heterografts
Immunohistochemistry
Female
Original Article
business
Protein Binding
Signal Transduction
TNF-α/MAPK (p38) pathway
Zdroj: Cancer Research and Treatment : Official Journal of Korean Cancer Association
ISSN: 2005-9256
1598-2998
Popis: Purpose Although cathepsin C (CTSC) has been reported to maintain malignant biological properties in various cancers, its functions in hepatocellular carcinoma (HCC) remain obscure. We aimed to investigate the potential role of CTSC in HCC. Materials and Methods HCC tissue microarrays (n=122) were employed to analyze the correlation between CTSC expression and clinicopathological characteristics through immunohistochemistry staining. Quantitative real-time polymerase chain reaction, western blot assay, Cell Counting Kit-8 assay, colony formation, cell migration, and invasion assays, xenograft mice model were adopted to validate what had been indicated by the bioinformatic web tools. Results By bioinformatic tools and tissue microarrays, CTSC was found upregulated in HCC compared with normal liver tissues, and its higher expression was correlated with poor prognosis of HCC patients (hazard ratio, 2.402; 95% confidence interval, 1.493 to 3.865; p < 0.001). By gain/loss-of-function assays, we implicated that CTSC functioned as an oncogene to promote the proliferation and metastasis of HCC cells. Mechanistically, we revealed that CTSC was involved in several cancer-related signaling pathways by Gene Set Enrichment Analysis, among which tumor necrosis factor α (TNF-α)/p38 pathway was verified to be activated by CTSC. Furthermore, we found that TNF-α could activate CTSC expression in a concentration- dependent manner. Ralimetinib, an oral p38 mitogen-activated protein kinase (MAPK) inhibitor could inhibit CTSC expression. These indicated a potential positive feedback loop between CTSC and TNF-α/MAPK (p38) signaling. Conclusion Taken together, CTSC plays an important role in the growth and metastasis of HCC and may be a promising therapeutic target upon HCC.
Databáze: OpenAIRE
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