Definition

Nectin is a cell adhesion molecule belonging to the immunoglobulin superfamily and is a homolog of the polio virus receptor (PVR/CD155), also known as the poliovirus receptor related protein (PVRL). Five members of the family have been identified, named Nectin-1, Nectin-2, Nectin-3, Nectin-4 and poliovirus receptor (PVR), of which PVR and Nectin-2 belong to some α herpesvirus receptors. In addition to Nectin-4, there are 2-3 heteromorphs formed due to different shearing methods, such as: Nectin-1 has three forms: α, β and δ, Nectin-2 has two forms, α and δ, Nectin-3 also has three forms: α, β and δ, of which α has the highest content in tissues.

The Nectins family, which includes 5 members, was first reported in 2001 that a gene fragment encoding Nectin-4 on human chromosome 1, containing 149475 base pairs, was later named AL162592, and it was confirmed that 9 exons in this fragment are involved in the encoding. Using the Northern blot technique, Nectin-4 was found to be expressed in both placental tissue and tracheal tissue, and expressed higher in placental tissue than in tracheal tissue, but not in other tissues in adults. Nectin-4(EDSS1, LNIR, PRR4, PVRL4, nectin-4) is abnormally highly expressed in bladder, lung, breast, and ovarian cancers and has been identified as a histological and serological marker of breast cancer. With the exception of Nectin-4, all members of the Nectin family are widely expressed in normal adult tissues such as epithelium, endothelium, hematopoiesis, neuronal cells, fibroblasts, and other cells. Among them, Nectin-1 and -2 are widely expressed in various tissues, and Nectin-3 is mainly expressed in the testes and placenta. As a result, Nectin-4 has been defined as a tumor-associated antigen with cancer-promoting properties in various cancers, playing a key role in tumor biology.

Fig. 1 Structural Diagram of Nectin-4

Function

Nectin-4 Promotes Tumor Angiogenesis

Recent studies have shown that Nectin-4 promotes tumor angiogenesis by activating the PI3K/AKT signaling pathway. Angiogenesis is an important basis for tumor growth, spread, invasion and expansion. During angiogenesis, where large amounts of vascular endothelial growth factor (VEGF) and increased microvascular density (IMD) are detected in the tumor microenvironment, upregulated Nectin-4 stimulates cell growth and has a critical effect on intratumoral angiogenesis. Downregulation of Nectin-4 inhibits VEGF expression and tumor angiogenesis in lung and colorectal cancer. Further studies have shown that the interaction between Nectin-4 and endothelial ITGB4 regulates the transcriptional activity of Src, PI3K, AKT, and inducible nitric oxide synthase, and ultimately induces angiogenesis.

Nectin-4 Promotes Tumor Cell Growth, Proliferation, and Migration

Decrease in Nectin-4 inhibits the proliferation of human PC cells. Low expression of Nectin-4 inhibits proliferation and migration of gallbladder cancer cells in vivo and in vitro. The underlying mechanism by which Nectin-4 promotes tumor cell growth, proliferation, and migration is through RAS-associated C3 botulinum toxin substrate 1 (RAC1) signaling activity. Rac1 is a member of the GTPases Rho family and has an important impact on the occurrence and development of tumors.

Nectin-4 Promotes EMT

EMT is the most critical cellular event before tumor migration, invasion, and metastasis. Nectin-4 regulates intercellular adhesion, reshapes the actin cytoskeleton, triggers EMT, and enhances the driving force of pseudopodia extension within tumor cells, ultimately leading to tumorigenesis and spread. Upregulation of Nectin-4 regulates actin fiber formation by binding to Afadin and activating the PI3K/AKT pathway, which in turn activates Rac1 to regulate EMT, which in turn controls cell shape rearrangement and metastasis.

Nectin-4 Can be Used as a Tumor Marker

The biological role of Nectin-4 in promoting proliferation, migration and metastasis during carcinogenesis is the focus of in-depth research. Although Nectin-4 expression levels or positivity rates vary in selected types of tumor specimens, most studies have confirmed Nectin-4 as a prognostic and diagnostic biomarker.

Fig. 2 Function diagram of Nectin-4

Clinical Application

Abnormal Expression

NIECTIN-4 is abnormally expressed in a variety of cancers, including bladder, breast, lung, pancreatic, and ovarian cancers. Among them, serum Nectin-4 levels were significantly elevated in patients with non-small cell lung cancer or serous ovarian cancer. Therefore, Nectin-4 can act as a marker to monitor cancer recurrence and metastasis. Nectin-4 expression has recently been found to be upregulated in some rare cancers, such as osteomas and hemangiomas and some papillary thyroid cancers, so Nectin-4 is a promising target in cancer treatment.

Vascular and Lymphatic Angiogenesis

After tumor cells proliferate, malignant cells tend to spread through angiogenesis or lymphangiogenesis. Nectin-4 is then involved in tumor metastasis through the angiogenic process. PI3K and AKT are also involved in the formation of new blood vessels through the soluble Nextin-4 extracellular region, which interacts with endothelial integrin-β4 to promote angiogenesis through Src, PI3K, Akt, and iNOS (inducible nitric oxide synthase).

In the in vitro angiosarcoma model, Src controls angiogenesis, in osteosarcoma, Nectin-4 induces the expression of PI3K/Akt/NF-κB by downregulating the expression of miR-520c-3p, thereby promoting the progression and metastasis of osteosarcoma, and nanoquinoline inhibits DNA repair and angiogenesis by regulating the inner and outer regions of Nextin-4.

Alpha Lifetech Inc. is dedicated to developing Nectin-4 diagnostic regents. Alpha Lifetech Inc. is a reputable supplier focusing on research, manufacture and sales of In Vitro Diagnostic (IVD) regents. All the IVD regents offered by Alpha Lifetech Inc. have undergone strict QC validation and are certified by the COA (certificate of analysis). Meanwhile, we can provide customized services according to customers' requirements. Alpha Lifetech Inc. is committed to supply high-quality, high-sensitivity antigen and antibody products for scientific research and industrial customers. In addition to regular small packages, Alpha Lifetech Inc.'s large-scale fermentation platform also allows us to provide raw material-grade IVD regents for the majority of industrial customers.

Please feel free to call our sales manager for technical information and quotation!