Steroid Receptor Coactivator-1 Expression Research Articles

Nuclear receptor coactivator SRC-1 promotes colorectal cancer progression through enhancing GLI2-mediated Hedgehog signaling.

Overexpression of nuclear coactivator steroid receptor coactivator 1 (SRC-1) and aberrant activation of the Hedgehog (Hh) signaling pathway are associated with various tumorigenesis; however, the significance of SRC-1 in colorectal cancer (CRC) and its contribution to the activation of Hh signaling are unclear. Here, we identified a conserved Hh signaling signature positively correlated with SRC-1 expression in CRC based on TCGA database; SRC-1 deficiency significantly inhibited the proliferation, survival, migration, invasion, and tumorigenesis of both human and mouse CRC cells, and SRC-1 knockout significantly suppressed azoxymethane/dextran sodium sulfate (AOM/DSS)-induced CRC in mice. Mechanistically, SRC-1 promoted the expression of GLI family zinc finger 2 (GLI2), a major downstream transcription factor of Hh pathway, and cooperated with GLI2 to enhance multiple Hh-regulated oncogene expression, including Cyclin D1, Bcl-2, and Slug. Pharmacological blockages of SRC-1 and Hh signaling retarded CRC progression in human CRC cell xenograft mouse model. Together, our studies uncover an SRC-1/GLI2-regulated Hh signaling looping axis that promotes CRC tumorigenesis, offering an attractive strategy for CRC treatment.

Steroid Receptor Coactivator-1 (SRC-1) Promoted Cell Metastasis of Gastric Cancer via VEGFC Activator by NF-κB.

The regulatory mechanism and function of steroid receptor coactivator-1 (SRC-1) was determined in vitro and the role played in gastric cancer was investigated. The study collected 64 patients with gastric cancer tissue and paracancerous tissue to investigate the clinical patterns of SRC-1 expression in gastric cancer. Quantitative polymerase chain reaction, Western blot, enzyme-linked immunosorbent assay, and immunofluorescence staining were used in this study. In patients with gastric cancer, SRC-1 serum expression levels were up-regulated. Over-expression of SRC-1 promoted cell growth and cell metastasis in vitro model of gastric cancer. However, down-regulation of SRC-1 reduced cell growth and cell metastasis in vitro model of gastric cancer. SRC-1 over-expression induced vascular endothelial growth factor C (VEGFC) protein expressions in vitro model by activation of nuclear factor-kappa B (NF-kB) expression. The inhibition of NF-κB reduced the pro-cancer effects of SRC-1 on cell growth and cell metastasis in vitro model of gastric cancer through inhibition of VEGFC expression. These results suggest that SRC-1 promoted cell metastasis of gastric cancer via VEGFC activator by NF-κB. These novel findings may shed further light on the pathogenesis of gastric cancer and on potential precursor markers.

SRC-1 Deficiency Increases Susceptibility of Mice to Depressive-Like Behavior After Exposure to CUMS.

Steroid receptor coactivator 1 (SRC-1) is one of the coactivators recruited by the nuclear receptors (NRs) when NRs are activated by steroid hormones, such as glucocorticoid. SRC-1 is abundant in hippocampus and hypothalamus and is also related to some major risk factors for depression, implicated by its reduced expression after stress and its effect on hypothalamus-pituitary-adrenal gland axis function. However, whether SRC-1 is involved in the formation of depression remains unclear. In this study, we firstly established chronic unpredictable stress (CUS) to induce depressive-like behaviors in mice and found that SRC-1 expression was reduced by CUS. A large number of studies have shown that neuroinflammation is associated with stress-induced depression and lipopolysaccharide (LPS) injection can lead to neuroinflammation and depressive-like behaviors in mice. Our result indicated that LPS treatment also decreased SRC-1 expression in mouse brain, implying the involvement of SRC-1 in the process of inflammation and depression. Next, we showed that the chronic unpredictable mild stress (CUMS) failed to elicit the depressive-like behaviors and dramatically promoted the expression of SRC-1 in brain of wild type mice. What's more, the SRC-1 knockout mice were more susceptible to CUMS to develop depressive-like behaviors and presented the changed expression of glucocorticoid receptor. However, SRC-1 deficiency did not affect the microglia activation induced by CUMS. Altogether, these results indicate a correlation between SRC-1 level and depressive-like behaviors, suggesting that SRC-1 might be involved in the development of depression induced by stress.

Steroid Receptor Coactivator-3 Is Required for Inhibition of the Intestinal Muscularis Inflammatory Response of Postoperative Ileus in Mice.

Inflammation theory has suggested that the pathogenesis of postoperative ileus (POI) involves the steroid receptor coactivator-3 (SRC-3). Therefore, we investigated the role of SRC-3 in the muscles of the small intestine using a mouse POI model. Here, we reported that intestinal manipulation (IM) significantly reduced the extent of phenol red migration in the entire gastrointestinal tract, and the calculated geometric center (GC) value in wild-type (WT) mice at 24 h after surgery was higher than that in the knockout (KO) mice and in the sham-operated control group. The expression of SRC-3 was upregulated in the mouse intestinal muscularis at 24 h after surgical manipulation, and the mRNA and protein levels of inflammatory cytokines were upregulated compared with those in the control group. At 24 h after IM, the number of neutrophils in the experimental group was significantly higher than that in the control group; in the IM group, the number of neutrophils in the SRC-3-/- mice was markedly higher than that in the WT mice. At 24 h after IM, the myeloperoxidase (MPO) activity in the experimental group was significantly higher than that in the control group. In the IM group, the MPO activity of the SRC-3-/- mice was markedly higher than that of the WT mice. In summary, proinflammatory cytokines, the number of neutrophils, and the MPO activity were significantly increased in the muscularis of the jejunum and ileum of KO mice after IM compared with those of the WT mice, indicating that SRC-3 might play a protective role in POI.

Steroid receptor coactivator-1 enhances the stemness of glioblastoma by activating long noncoding RNA XIST/miR-152/KLF4 pathway.

Glioblastoma (GBM) recurrence is attributed to the presence of therapy‐resistant glioblastoma stem cells. Steroid receptor coactivator‐1 (SRC‐1) acts as an oncogenic regulator in many human tumors. The relationship between SRC‐1 and GBM has not yet been studied. Herein, we investigate the role of SRC‐1 in GBM. In this study, we found that SRC‐1 expression is positively correlated with grades of glioma and inversely correlated with glioma patient’s prognosis. Steroid receptor coactivator‐1 promotes the proliferation, migration, and tumor growth of GBM cells. Notably, SRC‐1 knockdown suppresses the stemness of GBM cells. Mechanistically, long noncoding RNA X‐inactive specific transcript (XIST) is regulated by SRC‐1 at the posttranscriptional level and mediates the function of SRC‐1 in promoting stemness‐like properties of GBM. Steroid receptor coactivator‐1 can promote the expression of Kruppel‐like factor 4 (KLF4) through the XIST/microRNA (miR)‐152 axis. Additionally, arenobufagin and bufalin, SRC small molecule inhibitors, can reduce the proliferation and stemness of GBM cells. This study reveals SRC‐1 promotes the stemness of GBM by activating the long noncoding RNA XIST/miR‐152/KLF4 pathway and provides novel markers for diagnosis and therapy of GBM.

Steroid receptor coactivator-3 as a target for anaplastic thyroid cancer.

Anaplastic thyroid carcinoma (ATC) is an aggressive malignancy without effective therapeutic options to improve survival. Steroid receptor coactivator-3 (SRC-3) is a transcriptional coactivator whose amplification and/or overexpression has been identified in many cancers. In this study, we explored the expression of SRC-3 in ATCs and the effects of a new class of SRC-3 inhibitor-2 (SI-2) in human ATC cells (THJ-11T and THJ-16T cells) and mouse xenograft models to assess therapeutic potential of SI-2 for the treatment of ATC. SRC-3 protein abundance was significantly higher in human ATC tissue samples and ATC cells than in differentiated thyroid carcinomas or normal controls. SI-2 treatment effectively reduced the SRC-3 expression in both ATC cells and ATC xenograft tumors induced by these cells. Cancer cell survival in ATC cells and tumor growth in xenograft tumors were significantly reduced by SI-2 treatment through induction of cancer cell apoptosis and cell cycle arrest. SI-2 also reduced cancer stem-like cells as shown by an inhibition of tumorsphere formation, ALDH activity, and expression of stem cell markers in ATC. These findings indicate that SRC-3 is a potential therapeutic target for treatment of ATC patients and that SI-2 is a potent and promising candidate for a new therapeutic agent.

Steroid Receptor Coactivator-1 Expression in Pheochromocytoma: Clinicopathologic Correlation and Potential Diagnostic Pitfall.

Pheochromocytoma is a relatively uncommon tumor, and the histomorphologic and biochemical features that may portend malignant behavior have poor overall consensus across various proposed classification systems. Steroid receptor coactivator-1 (SRC-1) is a nuclear protein that mediates transcriptional activity. Current diagnostic applications of SRC-1 are limited, and include distinguishing adrenocortical carcinoma (ACC) from renal cell carcinoma, and other mimickers. SRC-1 expression in pheochromocytoma has not been previously studied. Pheochromocytoma cases were retrieved from our Urological Pathology database and expert consultation files of the senior author, from 2015 to 2019. Clinicopathological data were obtained. SRC-1 expression was scored systematically. Thirty-eight cases were included, with a female predominance, and a mean age of 52 years (range, 16 to 75 y). Seven patients had heritable mutations including RET (n=3), VHL (2), SDHB (1), and ATM and PDGFRA (1). Two patients developed clinical metastasis, who individually had ATM and PDGFRA mutations, and SDHB p.V140F mutation. All heritable tumors were positive for SRC-1, including diffuse/strong staining and intensity in the VHL cases, and diffuse staining with variable intensity in RET cases. Diffuse positivity was seen in most of our heritable cases, providing evidence for a putative link between RET and downstream SRC-1 signaling. An inverse relationship was observed between SRC-1 expression and Pheochromocytoma of the Adrenal Gland Scaled Score/tumor size, suggesting that SRC-1 phenotype may become muted in pheochromocytomas that have malignant potential. SRC-1 expression in aggressive pheochromocytomas, may also be a potential diagnostic pitfall in view of the fact that these tumors may be misinterpreted as ACC in the primary or metastatic setting.

Steroid receptor coactivator 3 inhibits hepatitis B virus gene expression through activating Akt signaling to prevent HNF4\u03b1 nuclear translocation

BackgroundChronic hepatitis B virus (HBV) infection is one of the most serious global public health problems. The role of steroid receptor coactivator 3 (SRC-3) in HBV biosynthesis is unknown. The aim of this study is to investigate the function of SRC-3 in regulating HBV biosynthesis both in vitro and in vivo and to identify the underlying mechanism.ResultsIn this study, we found that knockdown of SRC-3 could increase the levels of HBV mRNA and HBV proteins HBsAg and HBeAg in human liver cancer cell line HepG2 transfected with pHBV1.3 plasmids. In contrast, enforced expression of SRC-3 in SRC-3-knockdown HepG2 cells reduced the levels of HBV mRNA and HBV proteins HBsAg and HBeAg. Knockdown of SRC-3 dampened the Akt signaling, which has been shown to play a negative role in HBV transcription. Ectopic expression of constitutively activated Akt impaired the enhancement of HBV transcription by SRC-3 knockdown, indicating that SRC-3 inhibits HBV transcription by enhancing Akt signaling. Both SRC-3 and constitutively activated Akt could inhibit hepatocyte nuclear factor 4α (HNF4α)-mediated upregulation of HBV core promoter activity by preventing HNF4α nuclear translocation. Consistent with the in vitro results, in an in vivo chronic HBV replication mouse model developed by hydrodynamic injection of pHBV1.3 plasmids into mouse tail vein, enforced expression of SRC-3 in mouse liver reduced the levels of HBV mRNA in the liver and HBV antigens in serum, whereas knockout of SRC-3 in mouse increased the levels of HBV mRNA in the liver and HBV antigens in the serum.ConclusionOur study suggests that SRC-3 inhibits HBV gene expression by activating Akt signaling to prevent HNF4α nuclear translocation.

Steroid receptor coactivator-1 regulates glioma angiogenesis through polyomavirus enhancer activator 3 signaling.

Steroid receptor coactivator 1 (SRC-1) is a transcriptional coactivator for steroid receptors and other transcription factors. SRC-1 has been shown to play an important role in the progression of breast cancer and prostate cancer. However, its role in glioma progression remains unknown. Here, in this study, we report that SRC-1 is upregulated in the vessels of human glioma and exerts important regulatory functions. Specifically, SRC-1 expression significantly enhanced basic fibroblast growth factor (bFGF)-mediated angiogenesis in vivo. Downregulating of SRC-1 expression suppressed endothelial cell migration and tube formation in vitro and upregulated the expression of pro-angiogenic factors, including vascular endothelial growth factor (VEGF) and matrix metallopeptidase (MMP)-9 in glioma cells. These SRC-1-mediated effects were dependent on the activation of polyomavirus enhancer activator 3 (PEA3) transcriptional activity. VEGF and VEGF inducer GS4012 induced the direct binding of SRC-1 and PEA3 in glioma cells, and PEA3 could directly bind with VEGF and MMP-9 promoter under GS4012 treatment in glioma cell. The expression of pro-angiogenic factors induced by SRC-1 was abrogated by sh-PEA3 knockdown. Taken together, these novel outcomes indicated that SRC-1 modulated endothelial cell (EC) function and facilitated a pro-angiogenic microenvironment through PEA3 signaling. Moreover, a combination of targeting SRC-1 and PEA3 signaling in glioma could be a promising strategy for suppressing tumor angiogenesis.

SRC1 Deficiency in Hypothalamic Arcuate Nucleus Increases Appetite and Body Weight.

Appetite is tightly controlled by neural and hormonal signals in animals. In general, steroid receptor co-activator 1 (SRC1) enhances steroid hormone signalling in energy balance and serves as a common co-activator of several steroid receptors, such as estrogen and glucocorticoid receptors. However, the key roles of SRC1 in energy balance remain largely unknown. We first confirmed that SRC1 is abundantly expressed in the hypothalamic arcuate nucleus (ARC), which is a critical centre for regulating feeding and energy balance; it is further co-localised with agouti-related protein and proopiomelanocortin neurons in the arcuate nucleus. Interestingly, local SRC1 expression changes with the transition between sufficiency and deficiency of food supply. To identify its direct role in appetite regulation, we repressed SRC1 expression in the hypothalamic ARC using lentivirus shRNA and found that SRC1 deficiency significantly promoted food intake and body weight gain, particularly in mice fed with a high-fat diet. We also found the activation of the AMP-activated protein kinase (AMPK) signalling pathway due to SRC1 deficiency. Thus, our results suggest that SRC1 in the ARC regulates appetite and body weight and that AMPK signalling is involved in this process. We believe that our study results have important implications for recognising the overlapping and integrating effects of several steroid hormones/receptors on accurate appetite regulation in future studies.

Steroid receptor coactivator-1 interacts with NF-κB to increase VEGFC levels in human thyroid cancer.

Thyroid cancer is the most common endocrine cancer, and has a high incidence of lymphatic metastasis. Vascular endothelial growth factor C (VEGFC) is essential for development of lymphatic vessels and lymphatic metastases during carcinogenesis. Steroid receptor coactivator-1 (SRC-1) interacts with nuclear receptors and transcription factors to promote tumor proliferation and metastasis. However, the correlation between SRC-1 and VEGFC levels in the lymphatic metastases of thyroid cancer remains unclear. We analyzed 20-paired specimens of thyroid cancer tissue and normal thyroid tissue and found increased levels of SRC-1 and VEGFC proteins in 13/20 and 15/20 thyroid cancer specimens, respectively, when compared with those levels in specimens of normal thyroid tissue. A high level of SRC-1 expression was positively correlated with VEGFC and lymphatic endothelial cell marker LYVE-1 expression. Papillary thyroid carcinoma cell line TPC-1 displayed high levels of SRC-1 and VEGFC expression and was selected for stable knockdown of SRC-1 in vitro. Inhibition of SRC-1 significantly reduced the VEGFC levels in TPC-1 cells. We found that SRC-1 binds to transcription factor NF-kB (p50/p65), and that this coactivation complex directly promoted VEGFC transcription, which could be abrogated by SRC-1 knockdown. Up-regulated NF-kB signaling was also confirmed in thyroid cancer tissues. In vivo studies showed that SRC-1 knockdown restricted tumor growth, reduced the numbers of LYVE-1-positive lymphatic vessels, and decreased the levels of VEGFC in tumor tissues. These results suggest a tumorigenic role for SRC-1 in thyroid cancer via its ability to regulate VEGFC expression.

SRC-3 Plays a Critical Role in Human Umbilical Vein Endothelial Cells by Regulating the PI3K/Akt/mTOR Pathway in Preeclampsia.

Preeclampsia (PE) is currently thought to be characterized by oxidative stress which may lead to endothelial dysfunction. The normal function of vascular endothelium is essential to vascular homeostasis. Previous studies have shown that steroid receptor coactivator 3 (SRC-3) interacts with estrogen receptors (ERs) which are involved in the vasoprotective effects of estrogen and is also associated with cell migration, invasion, and inflammation; however, its role in PE remains unclear. The main purpose of this study is to identify the role of SRC-3 in the function of human umbilical vein endothelial cells (HUVECs) during the development of PE. Our study demonstrated that the expression of SRC-3 was significantly decreased in PE placentas compared to normal placentas. Additionally, lentivirus short hairpin RNA against SRC-3 and hypoxia/reoxygenation treatments attenuated migration and tube formation abilities and enhanced HUVEC apoptosis. Furthermore, we detected possible downstream in the PI3K/Akt/mammalian target of rapamycin (mTOR) signal pathway activity, which is involved in SRC-3-mediated HUVEC function. Our data suggest that oxidative stress plays a crucial role in controlling SRC-3 expression, which influences the migration and tube formation abilities of endothelial cells through the PI3K/Akt/mTOR signaling pathways. This action may then result in PE pathogenesis.

Silencing steroid receptor coactivator-1 in the nucleus of the solitary tract reduces estrogenic effects on feeding and apolipoprotein A-IV expression

We previously found that 17β-estradiol (E2) stimulates apolipoprotein A-IV (apoA-IV) gene expression in the nucleus of the solitary tract (NTS) of lean ovariectomized (OVX) rodents. Here we report that in the NTS of high-fat diet-induced obese (DIO) rats, the apoA-IV mRNA level is significantly reduced and that the estrogenic effects on apoA-IV gene expression and food intake are impaired. E2 regulates apoA-IV gene expression through its nuclear receptor α (ERα), which requires co-activators, such as steroid receptor coactivator-1 (SRC-1), to facilitate the transcription of targeted genes. Interestingly, SRC-1 gene expression is significantly reduced in DIO OVX rats. SRC-1 is colocalized with apoA-IV in the cells of the NTS and E2 treatment enhances the recruitment of ERα and SRC-1 to the estrogen response element at the apoA-V promoter, implying the participation of SRC-1 in E2's stimulatory effect on apoA-IV gene expression. Using small hairpin RNA (shRNA), which was validated in cultured neuronal cells, we found that SRC-1 gene knockdown specifically in the NTS significantly diminished E2's anorectic action, leading to increased food intake and body weight. More importantly, the stimulatory effect of E2 on apoA-IV gene expression in the NTS was significantly attenuated in SRC-1 knockdown rats. These results collectively demonstrate the critical roles of NTS SRC-1 in mediating E2's actions on food intake and apoA-IV gene expression and suggest that reduced levels of endogenous SRC-1 and apoA-IV expression are responsible for the impaired E2's anorectic action in obese females.

Progesterone Receptor Isoforms, Nuclear Corepressor-1 and Steroid Receptor Coactivator-1 and B-Cell Lymphoma 2 and Akt and Akt Phosphorylation Status in Uterine Myomas after Ulipristal Acetate Treatment: A Systematic Immunohistochemical Evaluation

Objective: To investigate whether ulipristal acetate (UPA) treatment modifies the expression of progesterone receptor (PR), its nuclear cofactors steroid receptor coactivator-1 (SRC1) and nuclear corepressor-1 (NCoR1), prosurvival factor B-cell lymphoma 2 (Bcl-2), and Akt in uterine myomas. Patients: Prospective study of 59 women with symptomatic myomas undergoing myomectomy. Forty-two patients were treated preoperatively with UPA; the remaining 17 were not and they served as controls. Method: Tissue microarrays were obtained from surgical specimens and immunohistochemistry was performed. Blinded quantification of expression of PR (PR-A vs. PR-B), coactivator SRC1 and corepressor NCoR1, and prosurvival factor Bcl-2, and Akt and evaluation of Akt phosphorylation levels. Results: Compared with the control group, UPA does not alter PR protein levels or expression patterns in myomas, and the PR-A/PR-B ratio was similar, as well as cytoplasmic or nuclear expression of cofactors SRC1 and NCoR1. Bcl-2 was heterogeneously expressed throughout the samples and no significant modification in expression was evidenced. No significant difference was found in Akt expression and phosphorylation between treated and untreated myomas. Conclusion: This study did not find any significant change in the expression of the studied factors in myomas after UPA exposure. In conclusion, various theories on myomas cells proposed on the basis of in vitro studies are not supported in vivo.

SRC3 expressed in BMSCs promotes growth and migration of multiple myeloma cells by regulating the expression of Cx43.

Interactions between bone marrow stromal cells (BMSCs) and multiple myeloma cells significantly contribute to the progression of multiple myeloma (MM). However, little is known about the molecular mechanisms that regulate these interactions. Connexin-43 (Cx-43) has been implicated in the interplay between BMSCs and MM cells. In this study, we hypothesized that the steroid receptor co-activator-3 (SRC3) expressed in BMSCs regulates the expression of Cx-43 to promote the proliferation and migration of myeloma cells. To address this, we co-cultured a human multiple myeloma cell line, RPMI-8226 transfected with either control BMSCs or sh-SRC3-BMSCs. We found that knocking down SRC3 expression in BMSCs inhibited the proliferation and migration of RPMI-8226 cells. In addition, we found that co-culturing RPMI 8266 cells with BMSCs increased Cx43 expression, while knocking down SRC3 expression in BMSCs decreased Cx43 expression. Moreover, our work revealed that SRC3 in BMSCs regulates Cx43 expression via the mitogen-activated protein kinase (MAPK) pathway. To validate this result in vivo, we knocked down SRC3 expression in BMSCs in nude mice and found that tumor growth and cell apoptosis were significantly decreased. In addition, mice treated with either RPMI 8266 cells overexpressing Cx43 or with a P38 MAPK inhibitor (SB202190) exhibited increased intratumoral leukocyte populations and promoted cell apoptosis in tumor tissue. Our findings demonstrate how SRC3 and Cx43 regulation between BMSCs and myeloma cells mediate cell growth and disease progression, with potential implications for prognosis and therapeutic interventions.

Sex differences of steroid receptor coactivator-1 expression after spinal cord injury in mice

Objective: The neural functional recovery of female is often better than that of male after spinal cord injury (SCI). Evidences show that estrogen can attenuate inflammation and promote the neural survival and regeneration after SCI. SRC-1 is an essential initiation factor for the estrogen-regulated target gene transcription and plays a key role in regulating estrogen activity. However, it is not known whether and how SRC-1 mediates the neural regeneration promoted by estrogen after SCI. Study of the sex differences and changes of SRC-1 expression after SCI will be helpful to understand the above questions. Methods: In this study, the sex differences of expressions of SRC-1 and cytoskeleton-associated protein Profilin-1 in normal and SCI mice were detected by immunohistochemistry at 1-, 3-, and 7 days after injury, respectively. Results: Although the SRC-1 expression in female mice was lower than that in males under normal conditions, its expression in females was more dominant after SCI. The expression of Profilin-1 in both sexes increased first, and then decreased at 3 days after injury. However, there was a second increase in females at 7 days after injury. Conclusion: Our study suggests that the more SRC-1 expression in females after SCI may play a role in improving the efficiency of estrogen function and thus, promote regeneration better. SRC-1 may also participate in the regulation of Profilin-1 in spinal cord, which is important in the assembly and extension of the axonal cytoskeleton during regeneration after SCI.

Honokiol inhibits bladder cancer cell invasion through repressing SRC-3 expression and epithelial-mesenchymal transition.

Urinary bladder cancer (UBC) is one of the most common urological cancer types. Muscle invasive bladder cancer possesses high propensity for metastasis with poor prognosis. Honokiol is a lignan isolated from Magnolia officinalis with high bioavailability and potent anticancer effects. The results of the present study demonstrated that honokiol significantly inhibited UBC cell migration and invasion in a dose-dependent manner compared with the vehicle-treated control group. In addition, honokiol treatment suppressed epithelial-mesenchymal transition by induction of E-cadherin and repression of N-cadherin. Honokiol was capable of significantly downregulating the expression of cell invasion-associated genes, steroid receptor coactivator-3 (SRC-3), matrix metalloproteinase (MMP)-2 and Twist1. Notably, the inhibition of UBC cell invasion by honokiol was reversed by reintroduction of oncoprotein SRC-3 expression, with the restoration of MMP-2 and Twist1, and reduction of E-cadherin expression. Furthermore, the results of the luciferase assay confirmed that SRC-3 could regulate Twist1 promoter activity. Taken together, the results of the present study suggest that honokiol is a promising agent against UBC cell invasion via downregulation of SRC-3 and its target genes.

MiR-137 inhibits the proliferation of human non-small cell lung cancer cells by targeting SRC3.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. The results of the present study demonstrate that high expression of microRNA (miR)-137 and low expression of steroid receptor coactivator-3 (SRC3) had a significant negative correlation in 40 NSCLC tissue samples. In addition, cell colony formation and proliferation was significantly reduced in miR-137-transfected A549 and NCI-H838 cells compared with scramble-transfected NSCLC cell lines. miR-137 was identified to induce G1/S cell cycle arrest and dysregulate the mRNA expression of cell cycle-associated proteins (proliferating cell nuclear antigen, cyclin E, cyclin A1, cyclin A2 and p21) in NSCLC cells. Notably, miR-137 could significantly suppress SRC3 3' untranslated region (UTR) luciferase-reporter activity, an effect that was not detectable when the putative 3'-UTR target-site was mutated, further clarifying the molecular mechanisms underlying the role of miR-137 in NSCLC. In conclusion, the results of the present study suggest that miR-137 suppresses NSCLC cell proliferation by partially targeting SRC3.

The molecular mechanisms and morphological manifestations of leiomyoma reduction induced by selective progesterone receptor modulators

to investigate the molecular mechanisms and morphological substrate of reduced uterine leiomyoma in patients receiving the selective progesterone receptor modulator (SPRM) ulipristal acetate for 3 months, by estimating the immunohistochemical expression of the markers steroid receptor coactivator 1 (SRC-1), nuclear receptor corepressor 1 (NCoR-1), ER, PgR, Ki-67, p16, TGF-β, and VEGF in tumor tissue. The investigation enrolled 75 women with uterine leiomyoma, menorrhagias, and anemia. Group 1 included 40 patients who were treated with ulipristal for 3 months, followed by laparoscopic myomectomy. Group 2 consisted of 35 patients who underwent surgery without previous preparation. The intra- and postoperative parameters and molecular and morphological changes in the myomatous nodules were comparatively analyzed in both groups. After 3 months of therapy initiation, menorrhagia completely ceased, myomatous nodules decreased in size (p<0.05), hemoglobin levels were elevated (p<0.01), and total intraoperative blood loss and operative time decreased in all the patients in Group 1. The morphological substrate of partial leiomyoma reduction was leiomyocyte apoptosis and dystrophy, tumor stroma sclerosis and hyalinosis with diminished Ki-67 expression and elevated p16 in the smooth muscle cells, trophic nodular tissue disorders exhibited by vascular wall sclerosis and lower VEGF and TGF-β expression, and leiomyocyte hormonal reception dysregulation that made itself evident through the reduced expression of SRC-1 with the unchanged expression of PR and ER and the maintained level of NCoR-1. The molecular mechanisms of tumor reduction involved the reduced Ki-67 expression and elevated p16, lower VEGF and TGF-β, diminished SRC-1 expression with the maintained level of PR, ER, and NCoR-1. Overall, this is suggestive of enhanced apoptosis and reduced leiomyoma proliferation and angiogenesis induced by SPRM and indicative of the expediency of using ulipristal acetate as a preoperative agent for organ-sparing surgery in reproductive-aged patients with uterine myoma, menorrhagias, and anemia.

Letrozole regulates actin cytoskeleton polymerization dynamics in a SRC-1 dependent manner in the hippocampus of mice

In the hippocampus, local estrogens (E2) derived from testosterone that is catalyzed by aromatase play important roles in the regulation of hippocampal neural plasticity, but the underlying mechanisms remain unclear. The actin cytoskeleton contributes greatly to hippocampal synaptic plasticity; however, whether it is regulated by local E2 and the related mechanisms remain to be elucidated. In this study, we first examined the postnatal developmental profiles of hippocampal aromatase and specific proteins responsible for actin cytoskeleton dynamics. Then we used aromatase inhibitor letrozole (LET) to block local E2 synthesis and examined the changes of these proteins and steroid receptor coactivator-1 (SRC-1), the predominant coactivator for steroid nuclear receptors. Finally, SRC-1 specific RNA interference was used to examine the effects of SRC-1 on the expression of these actin remodeling proteins. The results showed a V-type profile for aromatase and increased profiles for actin cytoskeleton proteins in both male and female hippocampus without obvious sex differences. LET treatment dramatically decreased the F-actin/G-actin ratio, the expression of Rictor, phospho-AKT (ser473), Profilin-1, phospho-Cofilin (Ser3), and SRC-1 in a dose-dependent manner. In vitro studies demonstrated that LET induced downregulation of these proteins could be reversed by E2, and E2 induced increase of these proteins were significantly suppressed by SRC-1 shRNA interference. These results for the first time clearly demonstrated that local E2 inhibition could induce aberrant actin polymerization; they also showed an important role of SRC-1 in the mediation of local E2 action on hippocampal synaptic plasticity by regulation of actin cytoskeleton dynamics.