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

Abstract

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 ! (TNF-!)/p38 pathway was verified to be activated by CTSC. Furthermore, we found that TNF-! 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-!/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.

Identification of 3-miRNA Signature for Predicting Prognosis in Patients with Hepatocellular Carcinoma

“…The target genes of the miRNAs were enriched in Ras signaling pathway, PI3K-Akt signaling pathway, MAPK signaling pathway and so on, which might be potential mechanisms of HCC vascular invasion. There were studies displayed that activated Ras signaling could promote HCC proliferation [38], and MAPK signaling pathway was associated with epithelial-tomesenchymal transition, invasion, and metastasis in HCC [39,40]. Additionally, activation of the PI3K/AKT pathway could also promote HCC progression [41].…”

miR‑642 serves as a tumor suppressor in hepatocellular carcinoma by regulating SEMA4C and p38&nbsp;MAPK signaling pathway

“…In the tumor development and metastasis, p38 MAPK signaling pathway is activated as a frequent event (28,29). p38 MAPK pathway was dysregulated in HCC tissues compared with the corresponding normal tissues (30). Increasing number of studies have demonstrated that miRNAs interacted with signaling pathways in a variety of cancers.…”

Inflammatory Cytokines in Cancer: Comprehensive Understanding and Clinical Progress in Gene Therapy

“…By attaching to TNF-α R-1 and TNF-α R-2 [ 26 ], the cytokine impacts tumor development via multiple mechanisms, such as contributing to EMT, boosting the cell proliferation rate and accelerating angiogenesis, among others [ 40 , 41 , 42 ]. The aberrant expression of TNF-α was found in a variety of neoplastic diseases, including prostate cancer, ovarian cancer, liver cancer and breast cancer [ 43 , 44 , 45 , 46 ]. The antitumor activities of TNF-α have been leveraged in cancer treatments [ 47 ].…”