Abstract
Lung cancer remains a huge challenge to public health because of its high incidence and mortality, and lung adenocarcinoma (LUAD) is the main subtype of lung cancer. Hypoxia-induced vascular endothelial growth factor (VEGF) release and angiogenesis have been regarded as critical events in LUAD carcinogenesis. In the present study, membrane progesterone receptor α (mPRα) is deregulated within LUAD tissue samples; increased mPRα contributes to a higher microvessel density (MVD) in LUAD tissues. mPRα knockdown in A549 and PC-9 cells significantly inhibited STAT3 phosphorylation, as well as HIF1α and VEGF protein levels, decreasing cancer cell migration and invasion. The in vivo xenograft model further confirmed that mPRα enhanced the aggressiveness of LUAD cells. Furthermore, mPRα knockdown significantly inhibited hypoxia-induced upregulation in HIF1α and VEGF levels, as well as LUAD cell migration and invasion. Under the hypoxic condition, conditioned medium (CM) derived from mPRα knockdown A549 cells, namely si-mPRα-CM, significantly inhibited HUVEC migration and tube formation and decreased VEGF level in the culture medium. In contrast, CM derived from mPRα-overexpressing A549 cells, namely mPRα-CM, further enhanced HUVEC migration and tube formation and increased VEGF level under hypoxia, which was partially reversed by STAT3 inhibitor Stattic. In conclusion, in LUAD cells, highly expressed mPRα enhances the activation of cAMP/JAK/STAT3 signaling and increases HIF1α-induced VEGF secretion into the tumor microenvironment, promoting HUVEC migration and tube formation under hypoxia.
Highlights
Lung cancer is one of the most commonly seen cancers with the second-highest incidence rate among men and women globally
The mRNA expression of mPRα-overexpressing vector (mPRα) was determined in collected (See figure on page.) Fig. 2 mPRα activates Cyclic AMP (cAMP)/JAK/STAT3 signaling pathway in lung adenocarcinoma (LUAD) cells A549 and PC-9 cells were transfected with siRNA for mPRα (si-mPRα) or mPRα and examined for (A) cAMP concentrations using a cAMP Direct Immunoassay kit; B vascular endothelial growth factor (VEGF) concentrations using ELISA; C the protein levels of p-STAT3, STAT3, VEGF, and HIF1α
Discussion mPRα deregulation was observed within LUAD tissue samples. mPRα knockdown in A549 and PC-9 cells significantly inhibited STAT3 phosphorylation, as well as HIF1α and VEGF protein levels, suppressing the capacity of LUAD cells to migrate and to invade
Summary
Lung cancer is one of the most commonly seen cancers with the second-highest incidence rate among men and women globally. Unlike lung squamous cell carcinoma, which is prone to occur in men and is closely related to smoking [4], LUAD is often in women who do not smoke [5, 6]. Previous studies indicate that the receptors of estrogen, ERα (estrogen receptor α) and ERβ (estrogen receptor β), appear to be expressed within pulmonary cancer/ LUAD, and both can mediate the oncogenic role of estrogen in lung cancer or act as oncogenic factors themselves [9,10,11]. One of the mPRs, mPRα, is expressed within various types of cancer cells, such as breast carcinoma cells [12], ovarian cancer cells [13], astrocytoma cells [14], and glioblastoma cells [15]. MPRα expression is upregulated in LUAD tissues, according to data from GEPIA (Gene Expression Profiling Interactive Analysis), the independent role of mPRα in LUAD remains unclear
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