Abstract
Epidemiological studies have demonstrated that type 2 diabetes mellitus (T2DM) and hyperinsulinemia are associated closely with endometrial carcinoma risk, although the molecular mechanism remains unclear. Insulin receptor isoformA expression is upregulated in many cancer cells and tissues, which suggests that IR-A-mediated signaling pathways may have important implications for cancer pathogenesis. We measured the expression of insulin receptor isoforms (IR-A and IR–B in the normal endometrium tissues, the endometrial carcinoma tissues and the endometrial carcinoma cell lines. We found that the total insulin receptor (IR) and IR-A expression mRNA levels and the ratio of IR-A to total IR in endometrial carcinoma specimens were significantly higher than them in control endometrial tissue specimens(P<0.05). Further analysis indicated that the tendency was more prominently in patients with T2DM. IR-A mRNA was differentially expressed in four endometrial carcinoma cell lines (Ishikawa, KLE, RL95-2 and HEC-1-A. RL95-2 cells have a low endogenous IR-A expression, and these were used to construct a stable cell line overexpressing IR-A. We found that IR-A overexpression significantly increased cell proliferation, the proportion of cells in S phase, activation of the Akt pathway and tumorigenicity of xenografts in nude mice. In contrast, there was no significant difference in the the percentage of apoptotic cells between cells overexpressing IR-A and control cells. Moreover, levels of phosphorylated ERK1/2 protein were significantly decreased in cells overexpressing IR-A relative to controls. These findings reveal the pivotal role of IR-A in endometrial cancer carcinogenesis, and suggest that the association of elevated IR-A levels with cell proliferation and tumorigenicity may be causally linked to its effect on the proportion of cells in S phase and the activation of the Akt pathway.
Highlights
Endometrial cancer is the third most common malignancy of the female genital tract reported in China
Previous studies have reported that insulin receptor (IR)-A is a high affinity receptor for insulin-like growth factor (IGF)-2 [10], To further confirm whether the endometrial cancer cell lines can secrete IGF-2, enzyme-linked immunosorbent assay (ELISA) was performed using cell culture supernatants from the HEC-1-A, Ishikawa, KLE, RL95-2-con and RL95-2-isoform A (IR-A) cell lines
We observed that IGF-2 secretion was highest in RL95-2–CON cells and reduced in RL95-2–IR-A, KLE, HEC-1-A and Ishikawa cells
Summary
Endometrial cancer is the third most common malignancy of the female genital tract reported in China. An improved understanding of the factors regulating endometrial cancer cell growth should lead to better treatment options. The insulin receptor (IR) belongs to a subfamily of receptor tyrosine kinases that includes the insulin-like growth factor (IGF) 1receptor(IGF-1R) and the insulin-receptor-related receptor. Members of this family of receptors are tetrameric proteins consisting of two extracellular α-subunits and two transmembrane β-subunits linked by disulfide bonds [2]. The presence (IR–B, or IR exon 11+) or absence (IR-A, or exon 11-) of these residues alters the functional properties of the isoform. IR-A has potent mitogenic and anti-apoptotic functions and plays a key role in cell proliferation [4]
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