LAMC1 is a prognostic factor and a potential therapeutic target in endometrial cancer

Abstract

Objective: With the emerging significance of genetic profiles in the management of endometrial cancer, the identification of tumor-driving genes with prognostic value is a pressing need. The LAMC1 gene, encoding the laminin subunit gamma 1 (LAMC1) protein, has been reported to be involved in the progression of various malignant tumors. In this study, we aimed to investigate the role of LAMC1 in endometrial cancer and elucidate the underlying mechanism.

Methods: We evaluated the immunohistochemical expression of LAMC1 in atypical endometrial hyperplasia and endometrial cancer. Within the endometrial cancer cases, we analyzed the association of LAMC1 overexpression with clinicopathological factors and prognosis. Furthermore, to indentify genes influenced by LAMC1 overexpression, we transfected HEC50B and SPAC-S cells with siRNA targeting LAMC1 and conducted microarray gene expression assays.

Results: While none of the atypical endometrial hyperplasia specimens exhibited LAMC1 overexpression, endometrial cancer possessed a significantly higher LAMC1 overexpression rate. LAMC1 overexpression was strongly associated with histological type, lymphovascular space invasion, lymph node metastasis, advanced International Federation of Gynecology and Obstetrics stage, and poor overall survival in endometrial cancer. Gene expression microarray analysis identified 8 genes correlated with tumor progression (LZTFL1, TAPT1, SEL1L, PAQR6, NME7, TMEM109, CCDC58, and ANKRD40) that were commonly influenced in HEC50B and SPAC-S by LAMC1 silencing.

Conclusion: LAMC1 overexpression is a potent biomarker for identifying endometrial cancer patients needing aggressive adjuvant therapy. We elucidated 8 candidate genes that may mediate progression of LAMC1 overexpressing cancer. Further investigation of the underlying mechanism should lead to the discovery of new therapeutic targets.

Keywords: Endometrial Cancer; Laminin; Transcript Expression Analysis.

Fig. 1. LAMC1 expression pattern in endometrial tissues. (A) Normal endometrium (proliferative phase). (B) Atypical endometrial hyperplasia. (C) Endometrioid carcinoma grade 1. (D) Endometrioid carcinoma grade 3. (E) Clear cell carcinoma. (A,B) There were evaluated as negative. (C-E) There were evaluated as positive for LAMC1 overexpression. Scale bars, 100 μm.

LAMC1, laminin subunit gamma 1.

Fig. 2. Kaplan-Meier curves representing the association between LAMC1 overexpression and (A) PFS and (B) OS rates. Log-rank tests indicated that patients with overexpression of LAMC1 had a poorer overall prognosis.

LAMC1, laminin subunit gamma 1; OS, overall survival; PFS, progression-free survival.

Fig. 3. Relative expression of genes in HEC50B and SPAC-S transfected with siRNA targeting LAMC1. Cells were transfected with either LAMC1 or control siRNAs for 48 hours. Silencing of LAMC1 and expression changes of genes identified by microarray analysis were confirmed. The p-values are as shown (Student's t-test). All quantitative data are expressed as means± standard deviation (n=3 experiments).

LAMC1, laminin subunit gamma 1.