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2018 ; 7
(1
): 3
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LRIG2 is a growth suppressor of Hec-1A and Ishikawa endometrial adenocarcinoma
cells by regulating PI3K/AKT- and EGFR-mediated apoptosis and cell-cycle
#MMPMID29358688
Suh DS
; Park SE
; Jin H
; Lee K
; Bae J
Oncogenesis
2018[Jan]; 7
(1
): 3
PMID29358688
show ga
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.