CD82 gene suppression in endometrial stromal cells leads to increase of the cell invasiveness in the endometriotic milieu

Abstract

Tetraspanin CD82 is a wide-spectrum tumor metastasis suppressor that inhibits motility and invasiveness of cancer cells. Endometriosis is a benign gynecological disorder, but appears malignant behaviors including invasion, ectopic implantation and recurrence. This study is to elucidate the role of CD82 expression regulation in the pathogenesis of endometriosis. The short interfering RNA silence was established to analyze the roles of CD82, chemokine CCL2, and its receptor CCR2 in the invasiveness of endometrial stromal cells (ESCs). We have found that the mRNA and protein levels of CD82 in the primary normal ESCs from endometrium without endometriosis are significantly higher than that of the primary ESCs from eutopic endometrium and ectopic tissue. CD82 inhibits the invasiveness of ESCs by downregulating CCL2 secretion and CCR2 expression via mitogen-activated protein kinase (MAPK) and integrinb1 signal pathway, and in turn upregulating the expression of TIMP1 and TIMP2 in an autocrine manner. The combination of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) with 17b-estradiol can promote the invasion of ESCs via suppressing CD82 expression and stimulating CCL2 secretion and CCR2 expression, and the enhanced interaction of CCL2-CCR2 recruits more macrophages into the ectopic milieu in a paracrine manner, which further downregulates CD82 expression in the ectopic ESCs. Our study has demonstrated for the first time that the abnormal lower CD82 expression in ESCs induced by TCDD and estrogen may be an important molecular basis of endometriosis pathogenesis through enhancing the CCL2 secretion and CCR2 expression and the invasion of ESCs via MAPK and integrinb1 signal pathway.

Chemokine CCL2 enhances survival and invasiveness of endometrial stromal cells in an autocrine manner by activating Akt and MAPK/Erk1/2 signal pathway

“…1F, right), and invasion ( Fig. 1G) (P< .01), which echoes our previous results (8). In addition, the proliferation, viability, and invasiveness of normal ESCs are lower than that of the eutopic ESCs.…”

“…Recent research has established that the up-regulation of survival-relative molecules and invasion-relative molecules may cooperatively contribute to survival and invasion of endometriosis, such as matrix metalloproteinases (MMPs) (8,9), survivin (9), proliferating cell nuclear antigen (PCNA), and cyclooxygenase (COX)-2 (10). Several investigators reported a relationship between CCL2 levels in serum (11,12) or peritoneal fluid (PF) (12,13) and endometriosis.…”

Tetraspanin CD82: a suppressor of solid tumors and a modulator of membrane heterogeneity

“…Thus, aberrantly high levels of CD82 in the decidua may block the invasion of trophoblasts, resulting in early pregnancy termination. Also, CD82 mRNA and protein levels become lower in the ESCs from a eutopic endometrium and ectopic endometriotic tissue in patients with endometriosis [102].…”

“…CD82 silencing in ESCs promotes the invasiveness of firsttrimester trophoblasts by increasing CCL2 secretion, CCR2 expression, integrin β1 levels, and MAPK signaling and by decreasing TIMP1 expression [101,102]. The reduced invasiveness of trophoblasts probably results from the increased release of TIMP1 by CD82-expressing, decidualized ESCs [101].…”

“…The reduced invasiveness of trophoblasts probably results from the increased release of TIMP1 by CD82-expressing, decidualized ESCs [101]. Reports on the role of CD82 in ESC movement are inconsistent [102,103].…”