LAMC1

Official Full Name

laminin subunit gamma 1

Organism

Homo sapiens

GeneID

3915

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, composed of 3 non identical chains: laminin alpha, beta and gamma (formerly A, B1, and B2, respectively), have 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 gamma chain isoform laminin, gamma 1. The gamma 1 chain, formerly thought to be a beta chain, contains structural domains similar to beta chains, however, lacks the short alpha region separating domains I and II. The structural organization of this gene also suggested that it had diverged considerably from the beta chain genes. Embryos of transgenic mice in which both alleles of the gamma 1 chain gene were inactivated by homologous recombination, lacked basement membranes, indicating that laminin, gamma 1 chain is necessary for laminin heterotrimer assembly. It has been inferred by analogy with the strikingly similar 3' UTR sequence in mouse laminin gamma 1 cDNA, that multiple polyadenylation sites are utilized in human to generate the 2 different sized mRNAs (5.5 and 7.5 kb) seen on Northern analysis. [provided by RefSeq, Aug 2011]

Synonyms

LAMB2;

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Detailed Information

Recent Progress

LAMC1 gene encodes an extracellular matrix protein, the laminin 1 chain, which is involved in several biological and pathological processes including tissue development, tumor cell invasion and metastasis.

The normal prostate as well as early stages and advanced prostate cancer (PCa) require a functional androgen receptor (AR) for growth and survival. The recent discovery of microRNAs (miRNAs) as novel effector molecules of AR revealed the existence of an intricate network between AR, miRNAs and downstream target genes. In order to investigate the functional significance of miR-29 in cancer cells and also to identify novel miR-29s-mediated cancer pathways and target genes involved in PCa oncogenesis and metastasis, a series of analysis was conducted by the researchers. Results demonstrated that miR-29s modulated the focal adhesion pathway. Moreover, the LAMC1 gene was a candidate target of miR-29s regulation. Luciferase assays showed that miR-29s directly regulated LAMC1. Silencing of LAMC1 significantly inhibited cell migration and invasion in cancer cells, and LAMC1 was upregulated in PCa. The miR-29s acted as tumor suppressors, contributing to cancer cell migration and invasion and directly targeting laminin signaling. Recognition of tumor-suppressive miRNA-mediated cancer pathways provided new insights into the potential mechanisms of PCa oncogenesis and metastasis, and suggested novel therapeutic strategies for treating this disease.

In a study using DUCaP cells, which are characterized by high content of wild-type AR and robust AR transcriptional activity, LAMC1 and myeloid cell leukemia 1 (MCL1) were identified as direct targets of miR-22 and miR-29a respectively, suggesting a tumor-suppressive role of these miRNAs. Indeed, transfection of miRNA mimics in PCa cells induced apoptosis and diminished cell migration and viability. Collectively, these data provided additional information regarding the complex regulatory machinery that may guide miRNAs activity in PCa, highlighting an important contribution of miRNAs in the AR signaling.

In another research, investigators detected a mutation in the extracellular matrix (ECM) protein-encoding gene NID1, in a family with autosomal dominant Dandy–Walker malformation and occipital cephaloceles. In a second family, further analysis identified a mutation in LAMC1, which encodes a NID1-binding partner. Structural modeling of the NID1–LAMC1 complex demonstrated that each mutation disrupts the interaction. These findings implicated the ECM in the pathogenesis of Dandy–Walker spectrum disorders (Fig.1).

Fig. 1. LAMC1 mutant sequence from Family 2 (top) compared to the normal LAMC1 sequence (bottom). (Yang et al, 2016)

In order to investigate the effects of microRNA-506(miR-506) on malignant phenotype of colorectal carcinoma cells and identify the target gene of miR-506 in colon carcinoma, researchers adopted the SW480 cell line for investigation. It was revealed that the number of migrated and invasive cells, viability and clonality in the miR-506 overexpression groups was reduced. Moreover, LAMC1 mRNA and protein levels in the miR-506 overexpression groups were lower than those in the control groups. These findings, taken together, suggested that LAMC1 is a direct target gene for miR-506 and miR-506 could inhibit the cell migration and invasion.

In another report, researchers confirmed a miR-124 mediated ceRNA (competing endogenous RNAs) crosstalk between LAMC1 and CD151 in hepatocellular carcinoma (HCC). miR-124 negatively regulates LAMC1 expression through two miRNA binding sites within its 3' untranslated region (3'UTR) and suppresses migration and invasion of HCC cells through regulating LAMC1. In clinical hepatic tissues, LAMC1 and CD151 mRNAs exhibit positive correlation. More importantly, LAMC1 MREs (miRNA response elements) promote HCC malignancy by absorbing miR-124 and also by assisting CD151 expression. Thus it was concluded that LAMC1 mRNA acts as a trans-regulator to stimulate CD151 expression by competing for miR-124 binding in HCC cells.

References:

Nishikawa, R., Goto, Y., Kojima, S., Enokida, H., Chiyomaru, T., & Kinoshita, T., et al. (2014). Tumor-suppressive microrna-29s inhibit cancer cell migration and invasion via targeting lamc1 in prostate cancer. International Journal of Oncology, 45(1), 401-10.
Darbro, B. W., Mahajan, V. B., Gakhar, L., Skeie, J. M., Campbell, E., & Wu, S., et al. (2013). Mutations in extracellular matrix genes nid1 and lamc1 cause autosomal dominant dandy–walker malformation and occipital cephaloceles. Human Mutation, 34(8), 1075-1079.
Pasqualini, L., Bu, H., Puhr, M., Narisu, N., Rainer, J., & Schlick, B., et al. (2015). Mir-22 and mir-29a are members of the androgen receptor cistrome modulating lamc1 and mcl-1 in prostate cancer. Molecular Endocrinology, 29(7), 1037-54.
Zu, C., Liu, T., & Zhang, G. (2016). Microrna-506 inhibits malignancy of colorectal carcinoma cells by targeting lamc1. Journal of Practical Medicine, 46(6), 666.
Yang, Z. P., Ma, H. S., Wang, S. S., Wang, L., & Liu, T. (2017). Lamc1 mrna promotes malignancy of hepatocellular carcinoma cells by competing for microrna-124 binding with cd151. Iubmb Life, 69(8), 595.
Zhang, Y., Xi, S., Chen, J., Zhou, D., Gao, H., & Zhou, Z., et al. (2017). Overexpression of lamc1 predicts poor prognosis and enhances tumor cell invasion and migration in hepatocellular carcinoma. Journal of Cancer, 8(15), 2992.

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