Journal Article

Novel LAMC2 fusion protein has tumor‐promoting properties in ovarian carcinoma

Miyagi, Yohei, Kato, Hisamori, Koshikawa, Naohiko, Mayeda, Akila, Seiki, Motoharu, Daisuke, Hoshino, Fukumura, Kazuhiro

2021

Overview

Laminins are heterotrimeric ECM proteins composed of α, β, and γ chains. The γ2 chain (Lm‐γ2) is a frequently expressed monomer and its expression is closely associated with cancer progression. Laminin‐γ2 contains an epidermal growth factor (EGF)‐like domain in its domain III (DIII or LEb). Matrix metalloproteinases can cleave off the DIII region of Lm‐γ2 that retains the ligand activity for EGF receptor (EGFR). Herein, we show that a novel short form of Lm‐γ2 (Lm‐γ2F) containing DIII is generated without requiring MMPs and chromosomal translocation between LAMC2 on chromosome 1 and NR6A1 gene locus on chromosome 9 in human ovarian cancer SKOV3 cells. Laminin‐γ2F is expressed as a truncated form lacking domains I and II, which are essential for its association with Lm‐α3 and ‐β3 chains of Lm‐332. Secreted Lm‐γ2F can act as an EGFR ligand activating the EGFR/AKT pathways more effectively than does the Lm‐γ2 chain, which in turn promotes proliferation, survival, and motility of ovarian cancer cells. LAMC2‐NR6A1 translocation was detected using in situ hybridization, and fusion transcripts were expressed in ovarian cancer cell tissues. Overexpression and suppression of fusion transcripts significantly increased and decreased the tumorigenic growth of cells in mouse models, respectively. To the best of our knowledge, this is the first report regarding a fusion gene of ECM showing that translocation of LAMC2 plays a crucial role in the malignant growth and progression of ovarian cancer cells and that the consequent product is a promising therapeutic target against ovarian cancers. Expression of LAMC2‐NR6A1 fusion transcripts in human ovarian carcinomas.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: AKT protein / Animal models / Animals / Cell culture / Cell Line, Tumor / Cell proliferation / Chromosome 1 / Chromosome 9 / Chromosome translocations / Cocarcinogenesis - genetics / Cocarcinogenesis - metabolism / Epidermal growth factor / Epidermal growth factor receptors / Extracellular matrix / Female / fusion gene / Fusion protein / Gene Expression Regulation, Neoplastic / Genes / Humans / Hybridization / Kinases / Laminin / Laminin - genetics / Laminin - metabolism / laminin‐γ2 / Ligands / Liver cancer / Matrix metalloproteinase / Mice / Mice, Inbred BALB C / Mice, Nude / Nuclear Receptor Subfamily 6, Group A, Member 1 - genetics / Nuclear Receptor Subfamily 6, Group A, Member 1 - metabolism / Oncogene Proteins, Fusion - genetics / Oncogene Proteins, Fusion - metabolism / Original / Ovarian cancer / Ovarian carcinoma / Ovarian Neoplasms - genetics / Ovarian Neoplasms - metabolism / Ovarian Neoplasms - pathology / Protein expression / Protein Subunits - genetics / Protein Subunits - metabolism / Proteins / RNA Interference / Therapeutic targets / Tumors / Xenograft Model Antitumor Assays - methods