Abstract
Hepatocellular carcinoma-related protein-1 (HCRP-1), a subunit of mammalian endosomal sorting complex required for transport-I (ESCRT-I), is frequently downregulated in various kinds of malignant tumors. The role of HCRP-1 in colorectal cancer (CRC) remains unknown. We investigate the clinical value of HCRP-1 and its impact on anoikis in CRC. The negative expression of HCRP-1 was significantly correlated with tumor size (P = 0.033), PT status (P = 0.001), TNM stage (P = 0.039), and histological grade (P = 0.01). Univariate and multivariate analyses revealed that HCRP-1 was an independent prognostic factor for CRC (hazard ratio (HR) = 0.237, P < 0.001 for 5-year overall survival). In the in vitro assay, we found that HCRP-1 depletion resulted in cell anoikis resistance. Knockdown of HCRP-1 suppressed Bcl-2 interacting mediator of cell death (BIM) expression, with phosphorylation of AKT and p-FoxO3a, which was reversed by AKT siRNA or AKT inhibitor. Further analysis showed that loss of HCRP-1 obviously increased the activation of EGFR. Inhibition of EGFR blocked si-HCRP1-mediated phosphorylation of EGFR, AKT, FoxO3a, and BIM expression. Moreover, the in vivo results revealed that loss of HCRP-1 promoted cancer metastasis. Our findings implied that reduced HCRP-1 expression in CRC resulted in anoikis resistance and contributed to CRC metastasis and poor prognosis. These data may help design effective therapy targeting HCRP-1 pathway to control colon cancer growth and metastasis.
Highlights
colorectal cancer (CRC) is the second most common cancer in females and the third in males, and the fourth highest reason of cancer-associated deaths all over the world[1]
The results revealed that loss of Hepatocellular carcinoma-related protein-1 (HCRP-1) promoted tumor metastasis in vivo and activated the EGFR and AKT signaling pathway, which was consistent with the results obtained in in vitro experiments
HCRP-1 was first cloned from hepatocellular carcinoma cell lines and was thought to be a growth inhibitory protein
Summary
CRC is the second most common cancer in females and the third in males, and the fourth highest reason of cancer-associated deaths all over the world[1]. Surgical resection is one of the most effective treatments for patients with CRC, 30% of patients still form tumor metastasis[2,3]. EGFR belongs to the ErbB family of transmembrane receptor tyrosine kinases, which is widely distributed on the surface of mammalian cell membranes. It plays an important role in governing multiple cellular processes, containing cell proliferation, survival, and migration[4,5]. Hyperactivation of EGFR-dependent signal transduction usually accompanies tumor development and leads to unfavorable clinical prognosis[6]. Targeting the EGFR pathway constitutes a potential treatment modality for human cancers
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