CEMIP, a Promising Biomarker That Promotes the Progression and Metastasis of Colorectal and Other Types of Cancer

Abstract

Originally discovered as a hypothetical protein with unknown function, CEMIP (cell migration-inducing and hyaluronan-binding protein) has been implicated in the pathogenesis of numerous diseases, including deafness, arthritis, atherosclerosis, idiopathic pulmonary fibrosis, and cancer. Although a comprehensive definition of its molecular functions is still in progress, major functions ascribed to CEMIP include the depolymerization of the extracellular matrix component hyaluronic acid (HA) and the regulation of a number of signaling pathways. CEMIP is a promising biomarker for colorectal cancer. Its expression is associated with poor prognosis for patients suffering from colorectal and other types of cancer and functionally contributes to tumor progression and metastasis. Here, we review our current understanding of how CEMIP is able to foster the process of tumor growth and metastasis, focusing particularly on colorectal cancer. Studies in cancer cells suggest that CEMIP exerts its pro-tumorigenic and pro-metastatic activities through stimulating migration and invasion, suppressing cell death and promoting survival, degrading HA, regulating pro-metastatic signaling pathways, inducing the epithelial-mesenchymal transition (EMT) program, and contributing to the metabolic reprogramming and pre-metastatic conditioning of future metastatic microenvironments. There is also increasing evidence indicating that CEMIP may be expressed in cells within the tumor microenvironment that promote tumorigenesis and metastasis formation, although this remains in an early stage of investigation. CEMIP expression and activity can be therapeutically targeted at a number of levels, and preliminary findings in animal models show encouraging results in terms of reduced tumor growth and metastasis, as well as combating therapy resistance. Taken together, CEMIP represents an exciting new player in the progression of colorectal and other types of cancer that holds promise as a therapeutic target and biomarker.

Keywords: CEMIP; EMT; KIAA1199; hyaluronic acid; hyaluronidase; metastasis.

Figure 1

The genomic organization and protein domains of CEMIP. (A). The genomic organization of the 29 exons that comprise the CEMIP gene. (B). The major domains that comprise the CEMIP protein. The numbers refer to the amino acid positions that flank the different domains. The length and position of exons as well as domains are true to scale.

Figure 2

Schematic representation of the proposed mechanism of action for CEMIP-mediated degradation of hyaluronan (HA). Extracellular CEMIP binds to high molecular weight (HMW) HA and internalizes it via clathrin-coated endocytosis after binding to annexin A1 (ANXA1). In the endosome, HMW-HA is degraded into low and intermediate (LMW/IMW) HA. The degraded HA fragments are subsequently released back into the extracellular milieu. HYAL represents a hypothetical bone fide hyaluronidase that might conceivably participate in CEMIP-mediated HA degradation.

Figure 3

Schematic representation of the involvement of CEMIP in various signaling pathways. Direct interaction partners of CEMIP related to Wnt, EGFR, and Ca²⁺ signaling pathways are indicated. BiP: binding immunoglobulin protein. ITPR3: 1,4,5-trisphosphate receptor type 3. MEK1: Mitogen-activated protein kinase kinase 1. OGT: O-GlcNAc transferase. PLXNA2: Plexin A2. PTP4A3: protein tyrosine phosphatase 4A3. WBP11: WW domain binding protein 11.