LAMA4

Official Full Name

laminin subunit alpha 4

Organism

Homo sapiens

GeneID

3910

Background

Laminins, a family of extracellular matrix glycoproteins, are the major noncollagenous constituent of basement membranes. They have been implicated in a wide variety of biological processes including cell adhesion, differentiation, migration, signaling, neurite outgrowth and metastasis. Laminins are composed of 3 non identical chains: laminin alpha, beta and gamma (formerly A, B1, and B2, respectively) and they form a cruciform structure consisting of 3 short arms, each formed by a different chain, and a long arm composed of all 3 chains. Each laminin chain is a multidomain protein encoded by a distinct gene. Several isoforms of each chain have been described. Different alpha, beta and gamma chain isomers combine to give rise to different heterotrimeric laminin isoforms which are designated by Arabic numerals in the order of their discovery, i.e. alpha1beta1gamma1 heterotrimer is laminin 1. The biological functions of the different chains and trimer molecules are largely unknown, but some of the chains have been shown to differ with respect to their tissue distribution, presumably reflecting diverse functions in vivo. This gene encodes the alpha chain isoform laminin, alpha 4. The domain structure of alpha 4 is similar to that of alpha 3, both of which resemble truncated versions of alpha 1 and alpha 2, in that approximately 1,200 residues at the N-terminus (domains IV, V and VI) have been lost. Laminin, alpha 4 contains the C-terminal G domain which distinguishes all alpha chains from the beta and gamma chains. The RNA analysis from adult and fetal tissues revealed developmental regulation of expression, however, the exact function of laminin, alpha 4 is not known. Tissue-specific utilization of alternative polyA-signal has been described in literature. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Aug 2011]

Synonyms

LAMA3; CMD1JJ; LAMA4*-1;

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Detailed Information

Recent Progress

In order to investigate the expression of the LAMA4 gene and its effect on invasion of HTR-8/SVneo (human villi trophoblast) cells and its role in the pathogenesis of preeclampsia, researchers investigated twenty-two patients with severe pre-eclampsia and 20 normal pregnant women were. Results showed that the expression of LAMA4 in severe pre-eclampsia group was dramatically lower than that of control group. Also, the expression of LAMA4 in HTR-8/SVneo cells was significantly decreased after siRNA treatments. Moreover, the invasive ability of HTR-8/SVneo cells was deduced after the deduction of LAMA4 expression. These findings suggest that damage of LAMA4 is probably involved in the mechanism of onset of preeclampsia by regulating invasion of trophoblast.

Given that the structure and molecular signature of tumor-associated vasculature are distinct from those of the host tissue, it is possible to selectively target the tumor blood vessels. To identify tumor-specific endothelial markers, researchers performed a microarray on tumor-associated and nonmalignant endothelium collected from patients with renal cell carcinoma (RCC), colorectal carcinoma, or colorectal liver metastasis. Melanoma cell adhesion molecule (MCAM) and its extracellular matrix interaction partner laminin alpha 4 (LAMA4) emerged as the most consistently expressed genes in tumor vessels. Notably, MCAM and LAMA4 were enhanced in locally advanced tumors as well as both the primary tumor and secondary metastases. Expression analysis in 18 different cancers and matched healthy tissues revealed vascular MCAM as highly specific in RCC, where it was induced strongly by VEGF (vascular endothelial growth factor), which is highly abundant in this disease. Overall, these findings highlight MCAM and LAMA4 as prime candidates for RCC prognosis and therapeutic targeting.

In addition, the present study investigated the association between the expression of ZEB1 and LAMA4 in gastric cancer and the possible underlying mechanisms beneath. The results indicated that LAMA4 upregulation was associated with higher grade tumors. LAMA4 knockdown significantly reduced MMP2 expression in gastric cancer cells and impaired the speed of wound healing and the invasive capability of the cancer cells. ZEB1 was strongly coexpressed with LAMA4 in some patients. Induced ZEB1 expression significantly increased LAMA4 expression at the mRNA and protein level in HGC6227 and SGC627901 cells. A dual luciferase assay confirmed that ZEB1 directly bound to the promoter of LAMA4. These results indicated that ZEB1 was able to epigenetically activate LAMA4 expression via binding to its promoter in gastric cancer cells. High LAMA4 expression was an independent indicator in patients with gastric cancer.

Other studies have shown that LAMA4 plays an important role in carcinogenesis. However, its molecular biological function in triple-negative breast cancer (TNBC) has not been entirely clarified. One study investigated the expression of LAMA4 in TNBC and its effect on cell proliferation, migration and invasion. Furthermore, researchers also identified the potential miRNA directly targeting LAMA4. Study showed LAMA4 mRNA and protein expression in TNBC tissue samples were elevated compared with adjacent normal tissue samples, and LAMA4 was mainly expressed in the cytoplasm of breast carcinoma cells (Fig.1). Knockdown of LAMA4 inhibited TNBC cell proliferation, migration and invasion in vitro. Moreover, further study revealed that LAMA4 was a putative target of miR-539, and miR-539 negatively regulated LAMA4 expression by directly targeting its 3′-UTR. These findings suggested that miR-539 suppressed the expression of LAMA4. LAMA4 plays an important role in tumor progression and may be an important target in treatment of TNBC.

Fig. 1. Expression of LAMA4 is increased at both protein and mRNA level in TNBC tissues. d-f LAMA4 was mainly expressed in the cytoplasm of breast carcinoma cells, d high expression; e low expression; f negative expression. (Yang et al, 2018)

References:

Wang, P., Shan, N., Wang, Y., & Qi, H. (2016). ‘Expression and function of lama4 in the placentas and trophoblast’. Journal of Chongqing Medical University.
Wragg, J. W., Finnity, J. P., Anderson, J. A., Ferguson, H. J., Porfiri, E., & Bhatt, R. I., et al. (2016). ‘Mcam and lama4 are highly enriched in tumor blood vessels of renal cell carcinoma and predict patient outcome’. Cancer Research, 76(8), 2314.
Shan, N., Zhang, X., Xiao, X., Zhang, H., Tong, C., & Luo, X., et al. (2015). ‘Laminin α4 (lama4) expression promotes trophoblast cell invasion, migration, and angiogenesis, and is lowered in preeclamptic placentas’. Placenta, 36(8), 809-820.
Yang, Z. X., Zhang, B., Wei, J., Jiang, G. Q., Wu, Y. L., & Leng, B. J., et al. (2018). ‘Mir-539 inhibits proliferation and migration of triple-negative breast cancer cells by down-regulating lama4 expression’. Cancer Cell International, 18(1), 16.
Zhong, Y. Z., Xue, S. L., Wei, Z., Bo, X. S., Xiao, C. Z., & Li, Q. Z., et al. (2015). ‘Mp47-02 microrna mir-200b is down-regulated and suppresses metastasis by targeting lama4 in renal cell carcinoma’. Journal of Urology,193(4), e552-e553.

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