Central Role of CEMIP in Tumorigenesis and Its Potential as Therapeutic Target

Abstract

CEMIP (KIAA1199) was identified as migratory indicator protein which had been crudely studied in the last decade. Firstly its mutation site was reported to cause hearing loss due to the folding change of protein structure, meanwhile the over-expression of CEMIP referred to dreadful invasion and uncontrolled proliferation of tumor with distant metastasis, dedifferentiation, and limited survival opportunity of patients. Especially, over-expressed CEMIP also protected malignant tumor from strict microenvironment in hypoxia, low glucose and cracked barrier, leading to enhanced adaptability of tumor by stimulating the Wnt, EGFR, FGFR pathway. Here, we intend to elaborate the clinical function and dysregulation of CEMIP under the tumorous circumstance since CEMIP plays an important role in cytokine pathway and its over-expression in tumors provide a novel target for individual therapy. Targeting CEMIP would thereby dysregulate the cytokine pathway which would in turn, decide the growth and death of the vicious tumour cells.

Keywords: CEMIP/KIAA1199; Cancer; Cytokine Signaling pathway; Hyaluronic acid..

Conflict of interest statement

Competing Interests: None declared.

Figures

Figure 1

The Simple Wnt/β-catenin pathway involving CEMIP. The Wnt signals will be captured by Frizzled receptors, then they are passed to β-catenin after forming complex with DSH. Over-expression of CEMIP will emphasize this formation and stimulate movement of DSH-Wnt complex towards nucleus. Also, the expression of nucleus-settled β-catenin positively induce the expression of CEMIP. Once bond to TCF complex, the transcription of small secreted protein would be started. Besides, CEMIP also stimulated the ITR3 leading the increase of Ca2+, which was also one of the Wnt signaling factor leading to intracellular ions disordered.

Figure 2

The EGFR signaling pathway involving CEMIP mediation. When EGF signals firstly attach HER2 receptor, heterodimerization and phosphorylation of HER2 and HER3 will be automatically processed leading to enablement of EGFR signaling pathway. The signal will head into two branches, descending activation and degradation where over-expressed CEMIP acts as connected junction. The light purple color represents CEMIP and its simple protein structure with specific binding site, wherein survival signal Src targeted 60AA near N-terminal, and NRG1 bond to N-terminal. Src branch towards Semaphorin-3A-meidated survive and NRG1 lead to proliferation through activation of MEK1. Plexin A2 bond to G8 domain of C-terminal initiating suppression of apoptosis. The dashed arrows describe the EGF signaling routine, so do the curved arrows. Thick line from Plexin A2 to Semaphorin 3A means it cuts off the delivery of apoptotic signal to Semaphorin 3A. The participation of over-expressed CEMIP also prevent EGF signals from consumption of lysosomal enzyme (LAMP2).