Abstract
Although endometrial cancer is the most common type of gynecological malignancy in developed countries, its molecular etiology is not well understood. Leucine-rich repeat and immunoglobulin-like domain 2 (LRIG2) is an evolutionarily conserved gene, but its functions in the endometrium are unknown. In this study, we found that LRIG2 is highly downregulated in endometrial adenocarcinoma patients and that it functions as a tumor suppressor. LRIG2 induced the mitochondrion-mediated apoptotic pathways by regulating stoichiometric balance among BCL-2 family proteins, whereby pro-survival members, MCL-1 and BCL-xL, were downregulated and pro-apoptotic BAK and BAX were upregulated. LRIG2 also inhibited proliferation of the Hec-1A and Ishikawa endometrial adenocarcinoma cells by upregulating p21. LRIG2 induced BAX- and BAK-dependent cell death that was efficiently prevented by MCL-1 overexpression. Furthermore, we found that LRIG2 unexpectedly phosphor-activates phosphoinositide 3-kinase (PI3K)/AKT and epidermal growth factor receptor (EGFR), which are conventionally accepted as survival signaling cues in diverse types of cancer. We observed that PI3K/AKT and EGFR serve as key kinases that have roles as growth suppressors of Hec-1A endometrial cancer cells by mediating the LRIG2-induced modulation of the BCL-2 family of proteins and p21. In vivo delivery of antisense DNAs against LRIG2 promoted the Hec-1A endometrial tumor growth in a xenograft mouse model, and immunoblotting of these tumor extracts showed consistent modulation of AKT, EGFR, the BCL-2 family members, and p21. Thus, our results demonstrated that LRIG2 is a growth suppressor of endometrial adenocarcinoma cells.
Highlights
Endometrial cancer is the most frequently occurring gynecological cancer in developed countries, and its rapidly increasing incidence causes great concern[1]
Here, we identified, for the first time, that LRIG2 is downregulated in endometrial adenocarcinoma tissues of patients and functions as a growth suppressor by promoting apoptotic cell death and cell-cycle arrest in Hec1A and Ishikawa endometrial carcinoma cells
LRIG2 activated epidermal growth factor receptor (EGFR) by stimulating phosphorylation of its tyrosines 1068, 1086, and 1101, and this response was associated with decreased MCL-1 and increased BAK, BAX, and p21 levels. These results indicate that phosphoinositide 3-kinase (PI3K)/AKT and EGFR pathways are key mediators of the antitumor activities of LRIG2
Summary
Endometrial cancer is the most frequently occurring gynecological cancer in developed countries, and its rapidly increasing incidence causes great concern[1]. Endometrial carcinoma is the major uterine cancer comprising 80–90% of cases[2]. The molecular mechanisms underlying development of endometrial. The protein family containing leucine-rich repeats and immunoglobulin-like domains (LRIG) is an evolutionarily conserved group of proteins with a single transmembrane domain[5,6]. Three homologs, LRIG1, LRIG2, and LRIG3, have been described. 54% of amino acid identity with LRIG1 and LRIG3, respectively[7,8,9]. Functions of the human LRIG family remain enigmatic[6], as only scarce relevant information is available. Comparative analysis of LRIG2 mRNA abundance in human organs showed its predominant
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