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

Laminins are heterotrimeric ECM proteins composed of alpha, beta, and gamma chains. The gamma 2 chain (Lm-gamma 2) is a frequently expressed monomer and its expression is closely associated with cancer progression. Laminin-gamma 2 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-gamma 2 that retains the ligand activity for EGF receptor (EGFR). Herein, we show that a novel short form of Lm-gamma 2 (Lm-gamma 2F) 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-gamma 2F is expressed as a truncated form lacking domains I and II, which are essential for its association with Lm-alpha 3 and -beta 3 chains of Lm-332. Secreted Lm-gamma 2F can act as an EGFR ligand activating the EGFR/AKT pathways more effectively than does the Lm-gamma 2 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.

Automated summary

Laminins, composed of alpha, beta, and gamma chains, play a critical role in cancer progression. A novel short form of Lm-gamma 2 (Lm-gamma 2F) can activate the EGFR/AKT pathways more effectively, promoting proliferation and motility of ovarian cancer cells. The translocation between LAMC2 and NR6A1 genes is crucial for the malignant growth and progression of ovarian cancer cells.