RESUMEN
Toll-like receptor (TLR) 2 is a key regulator of innate immune responses and has been shown to play an important role in inflammation-associated cancers. In this study, we aimed to evaluate the role of TLR2 in colorectal cancer (CRC). We demonstrated that TLR2 mRNA and protein expression was significantly upregulated in tumors from CRC patients and indicated poor prognosis. Using the TLR2 agonist Pam3Cys (P3C) to activate TLR2 signaling in human CRC cell lines, we showed that TLR2 drives cellular proliferation, which was dependent upon PI3K/Akt and NF-κB signaling pathways and was associated with the upregulation of anti-apoptotic genes BCL2A1, WISP1 and BIRC3. Likewise, pharmacological blockade of PI3K/Akt and NF-κB pathways mitigated the CRC pro-survival effects of TLR2 stimulation. Furthermore, genetic ablation of TLR2 using CRISPR/Cas9 suppressed CRC cell proliferation, invasion and migration. Taken together, these findings demonstrate that TLR2 plays an important role in colorectal tumorigenesis and may represent a promising therapeutic target in CRC.
Asunto(s)
Neoplasias Colorrectales/metabolismo , Receptor Toll-Like 2/metabolismo , Animales , Proteína 3 que Contiene Repeticiones IAP de Baculovirus/genética , Proteínas CCN de Señalización Intercelular/genética , Línea Celular Tumoral , Proliferación Celular , Neoplasias Colorrectales/genética , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Antígenos de Histocompatibilidad Menor/genética , FN-kappa B/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , ARN Mensajero/metabolismo , Transducción de Señal , Receptor Toll-Like 2/genéticaRESUMEN
PURPOSE: Recent studies have determined that cartilage oligomeric matrix protein (COMP) plays a vital role in carcinogenesis. We sought to clarify the role of COMP in colon cancer. METHODS: We investigated gene expression data from The Cancer Genome Atlas (TCGA) dataset. Tissue microarrays (TMA) containing paired samples from 253 patients with colon cancer were subjected to immunostaining. COMP levels in serum of colon cancer patients and healthy donors were measured with ELISA. We established COMP-knockout cells using the CRISPR/Cas9 system and COMP-overexpressing cells using lentiviral vectors to detect the effects of COMP on colon cancer cells using Cell Counting Kit-8 (CCK8), colony formation, apoptosis detection kit, and tumorigenesis assays in nude mice. RESULTS: The analysis of TCGA dataset and the results of the TMA suggested that COMP expression levels were significantly higher in cancer tissues than in adjacent normal tissues. Moreover, high COMP expression was correlated with the poor outcome of colon cancer patients. COMP levels in the sera of preoperative patients with colon cancer were much higher than those in healthy donors and were significantly reduced after colectomy. Colon cancer cells without COMP were defective with respect to the ability to proliferate, colony formation, the ability to resist 5-Fluorouracil-induced apoptosis and the growth of xenograft tumors in mice. Contrasting results were observed in COMP overexpressed cells. COMP promoted colon cancer cell proliferation partially through the activation of PI3K/ Akt/ mTOR/ p70S6K pathway. CONCLUSIONS: COMP may be a novel prognostic indicator and biomarker and also a potential therapeutic target for colon cancer.