TRIM58 functions as a tumor suppressor in colorectal cancer by promoting RECQL4 ubiquitination to inhibit the AKT signaling pathway.

BACKGROUND: This study aimed to investigate the underlying molecular mechanisms of TRIM58 in the development of colorectal cancer (CRC). CRC is one of the most common cancers of the digestive tract worldwide. The ubiquitin-proteasome system regulates many oncogenic or tumor-suppressive proteins. TRIM58, an E3 ubiquitin ligase and a member of the tripartite motif protein family, is a potential prognostic marker that indicates poor prognosis in cancer. Currently, the precise molecular mechanisms for the TRIM58-mediated CRC progression remain unclear. METHODS: To examine the effects of TRIM58 on cell viability, cell cycle progression, and apoptosis in CRC, Cell Counting Kit-8 and flow cytometry assays were employed. The AKT inhibitor LY294002 was used to examine the effects of AKT signaling on TRIM58-mediated cell viability, cell cycle progression, and apoptosis in CRC. Additionally, Co-IP and ubiquitination assays were used to examine the correlation between TRIM58 and RECQL4. RESULTS: TRIM58 overexpression inhibited CRC cell viability and promoted cell cycle arrest and apoptosis, in which the TRIM58 knockdown demonstrated inversed effects via the AKT signaling pathway. TRIM58 inhibited RECQL4 protein levels through its ubiquitin ligase activity, and RECQL4 overexpression inhibited TRIM58 overexpression-mediated CRC cell viability, cell cycle progression, and apoptosis. The downregulation of TRIM58 and upregulation of RECOL4 were observed in human CRC tissue, and TRIM58 demonstrated antitumor effects in CRC-induced tumor growth in a mouse model. CONCLUSIONS: TRIM58 acts as a tumor suppressor in CRC through the promotion of RECQL4 ubiquitination and inhibition of the AKT signaling pathway and may be investigated for the successful treatment of CRC.

High expression of P2X7R is an independent postoperative indicator of poor prognosis in colorectal cancer.

The purinergic P2X7 receptor (P2X7R) is a master regulator of inflammation and inflammation-related diseases. Recently, P2X7R has been reportedly involved in carcinogenesis and tumor progression. In this study, we investigated the expression pattern and prognostic merit of P2X7R in human colorectal cancer (CRC). The expression profile of P2X7R in 12 pairs of CRC and non-tumorous specimens was evaluated using Western blotting analysis. Additionally, we performed immunohistochemistry (IHC) on 116 paraffin-embedded CRC specimens, and evaluated the correlation between P2X7R expression and clinicopathological factors. P2X7R was overexpressed in CRC samples, compared with adjacent non-tumorous ones. High P2X7R expression significantly correlated with tumor size (P = .0177), Lymph node metastasis (P = .0128), and TNM stage (P = .0081). Furthermore, univariate and multivariate Cox regression analyses revealed that P2X7R expression could serve as an independent prognostic factor for poor overall survival (P = .0197). Treatment with P2X7R agonist BzATP led to the activation of Akt and NF-κB pathways. Consequently, we revealed that BzATP accelerated the proliferation of CRC cells, whereas co-incubation with PI3K/Akt inhibitor LY294002 significantly impaired BzATP-induced proliferation of CRC cells. Our findings implied that P2X7R may serve as a valuable prognostic indicator and promising therapeutic target of CRC.

Cortactin promotes colon cancer progression by regulating ERK pathway.

Cortactin is upregulated in various cancers including breast cancer, head and neck squamous cell carcinoma and gastric cancer. However, the role of cortactin in the pathogenesis of colon cancer remains unclear. mRNA expression of cortactin in colon cancer samples and cell lines was detected by quantitative real-time PCR (qRT-PCR), while protein expression of cortactin in colon cancer tissues and adjacent non-cancer tissues was assessed by immunohistochemistry. The role of cortactin in regulation of the proliferation of colon cancer derived cells were investigated both in vitro and in vivo. In the total of 60 paired colon cancer specimens, compared with the adjacent non-cancer tissues, the expression of cortactin mRNA was upregulated in 45 (75.0%). Immunohistochemical analysis showed significantly increased cortactin expression in colon cancer (42/60, 70.0%) compared to control tissues (18/60, 30.0%). Overexpression of cortactin promoted HCT116 cellular colony formation and tumor growth. Conversely, cortactin knockdown inhibited these effects in SW480 cells. Mechanistic analyses indicated that cortactin was able to activate the EGFR-ERK signaling pathway. Additionally, cortactin expression was associated with tumor size, tumor stages and lymphatic invasion, increased cortactin expression predicts poor prognosis in patients with colon cancer. In summary, cortactin demonstrated the promotive effect in human colon cancer cell growth and tumorigenicity. These results indicated that cortactin may serve as an effective target for gene therapy.