Yuan Xiang

STAT3 is required for MiR-17-5p-mediated sensitization to chemotherapy-induced apoptosis in breast cancer cells

Signal transducer and activator of transcription 3 (STAT3) controls cell survival, growth, migration, and invasion. Here, we observed that STAT3 exerted anti-apoptotic effects in breast cancer cells. On the other hand, miR-17-5p induced apoptosis in breast cancer cells, and overexpression of miR-17-5p sensitized MCF-7 cells to paclitaxel-induced apoptosis via STAT3. Overexpression of STAT3 in MCF-7 cells decreased paclitaxel-induced apoptosis, but STAT3 knockout abolished the miR-17-5p-induced increases in apoptosis. Finally, miR-17-5p promoted apoptosis by increasing p53 expression, which was inhibited by STAT3. These results demonstrate a novel pathway via which miR-17-5p inhibits STAT3 and increases p53 expression to promote apoptosis in breast cancer cells.

MiR-93-5p inhibits the EMT of breast cancer cells via targeting MKL-1 and STAT3

ABSTRACT Epithelial‐mesenchymal transition (EMT) plays an important role in breast cancer cell metastasis. Both (megakaryoblastic leukemia)/myocardin‐like 1 (MKL‐1) and Signal transducer and activator of transcription 3 (STAT3) have been implicated in the control of cellular metabolism, survival and growth. Our previous study has shown that cooperativity of MKL‐1 and STAT3 promoted breast cancer cell migration. Herein, we demonstrate a requirement for MKL‐1 and STAT3 in miRNA‐mediated cellular EMT to affect breast cancer cell migration. Here we show that cooperativity of MKL‐1 and STAT3 promoted the EMT of MCF‐7 cells. Importantly, MKL‐1 and STAT3 promoted the expression of Vimentin via its promoter CArG box. Interestingly, miR‐93‐5p inhibits the EMT of breast cancer cells through suppressing the expression of MKL‐1 and STAT3 via targeted their 3′UTR. These results demonstrated a novel pathway through which miR‐93‐5p regulates MKL‐1 and STAT3 to affect EMT controlling breast cancer cell migration. HighlightsCooperativity of MKL‐1 and STAT3 promoted the EMT of MCF‐7 cells.Cooperativity of MKL‐1 and STAT3 promoted the expression of Vimentin via its promoter CArG box.MiR‐93‐5p inhibits the EMT of MCF‐7 cells through suppressing MKL‐1 and STAT3 via targeted their 3′UTR.

Myocardin inhibits estrogen receptor alpha-mediated proliferation of human breast cancer MCF-7 cells via regulating MicroRNA expression

Myocardin is frequently repressed during human malignant transformation, and restoration of myocardin expression in sarcoma cells contributes to the inhibition of malignant growth. However, its role in breast carcinoma has barely been addressed. Here, we reported that myocardin could inhibit the proliferation of MCF‐7 cells. Notably, we show that myocardin inhibited ERα‐mediated proliferation of breast cancer MCF‐7 via impairing ER‐dependent transcriptional activation, mainly through the inhibition of the activity of ERα. Importantly, the molecular mechanism for the inhibition of the ERα‐mediated proliferation is that myocardin inhibited the transcription and expression of ERα‐induced PCNA, Ki‐67, and E2F1 to impair ERα‐mediated proliferation of breast cancer MCF‐7. Interestingly, myocardin significantly enhanced the transcription and expression of miR‐885 depending on the CArG box in miR‐885 promoter, and miR‐885 targeted the 3′ untranslated regions (UTR) of E2F1 to silence the expression of E2F1. Thus, our data provided important and novel insights into how myocardin may deeply influence ERα‐mediated breast cancer proliferation. In conclusion, myocardin could be seen as a breast cancer tumor suppressor so that it will provide new ideas for the treatment of breast cancer.

MRTF-A-miR-206-WDR1 form feedback loop to regulate breast cancer cell migration

ABSTRACT Breast cancer is the leading cause of cancer death in women worldwide which is closely related to metastasis. Our previous study has shown that MRTF‐A promote the migration of MDA‐MB‐231 cells and WDR1 promotes breast cancer cell migration. But the exact molecular mechanism on metastasis is still not fully understood, we now report that WDR1 enhanced the effect of MRTF‐A induced‐MDA‐MB‐231 cell migration by promoting the expression of the EMT markers and migration markers via RhoA‐MRTF‐A signaling pathway. Importantly, WDR1 promoted the nuclear importion of MRTF‐A by affecting the expression of nuclear transport protein importin. But WDR1 did not affect the expression of MRTF‐A. Interestingly, MRTF‐A promoted the expression of miR‐206 via its promoter CArG box but miR‐206 inhibits the migration of breast cancer cells through suppressing the expression of WDR1 and MRTF‐A via targeted their 3′UTR. Our data thus provide important and novel insights into MRTF‐A‐miR‐206‐WDR1 form feedback loop to regulate breast cancer cell migration. HIGHLIGHTSWDR1 enhanced the effect of MRTF‐A induced cell migration via RhoA‐MRTF‐A signaling pathway.WDR1 promoted the nuclear importion of MRTF‐A.MRTF‐A promoted the expression of miR‐206 via its promoter CArG box.miR‐206 inhibits cell migration through suppressing the expression of WDR1 and MRTF‐A.MRTF‐A‐miR‐206‐WDR1 form feedback loop to regulate breast cancer cell migration.

VEGF-A Stimulates STAT3 Activity via Nitrosylation of Myocardin to Regulate the Expression of Vascular Smooth Muscle Cell Differentiation Markers

Vascular endothelial growth factor A (VEGF-A) is a pivotal player in angiogenesis. It is capable of influencing such cellular processes as tubulogenesis and vascular smooth muscle cell (VSMC) proliferation, yet very little is known about the actual signaling events that mediate VEGF-A induced VSMC phenotypic switch. In this report, we describe the identification of an intricate VEGF-A-induced signaling cascade that involves VEGFR2, STAT3, and Myocardin. We demonstrate that VEGF-A promotes VSMC proliferation via VEGFR2/STAT3-mediated upregulating the proliferation of markers like Cyclin D1 and PCNA. Specifically, VEGF-A leads to nitrosylation of Myocardin, weakens its effect on promoting the expression of contractile markers and is unable to inhibit the activation of STAT3. These observations reinforce the importance of nitric oxide and S-nitrosylation in angiogenesis and provide a mechanistic pathway for VEGF-A-induced VSMC phenotypic switch. In addition, Myocardin, GSNOR and GSNO can create a negative feedback loop to regulate the VSMC phenotypic switch. Thus, the discovery of this interactive network of signaling pathways provides novel and unexpected therapeutic targets for angiogenesis-dependent diseases.

ERα inhibited myocardin-induced differentiation in uterine fibroids

Abstract Uterine fibroids, also known as uterine leiomyomas, are a benign tumor of the human uterus and the commonest estrogen‐dependent benign tumor found in women. Myocardin is an important transcriptional regulator in smooth and cardiac muscle development. The role of myocardin and its relationship with ER&agr; in uterine fibroids have barely been addressed. We noticed that the expression of myocardin was markedly reduced in human uterine fibroid tissue compared with corresponding normal or adjacent myometrium tissue. Here we reported that myocardin induced the transcription and expression of differentiation markers SM22&agr; and alpha smooth muscle actin (&agr;‐SMA) in rat primary uterine smooth muscle cells (USMCs) and this effect was inhibited by ER&agr;. Notably, we showed that, ER&agr; induced expression of proliferation markers PCNA and ki‐67 in rat primary USMCs. We also found ER&agr; interacted with myocardin and formed complex to bind to CArG box and inhibit the SM22&agr; promoter activity. Furthermore, ER&agr; inhibited the transcription and expression of myocardin, and reduced the levels of transcription and expression of downstream target SM22&agr;, a SMC differentiation marker. Our data thus provided important and novel insights into how ER&agr; and myocardin interact to control the cell differentiation and proliferation of USMCs. Thus, it may provide potential therapeutic target for uterine fibroids.

Myocardin and Stat3 act synergistically to inhibit cardiomyocyte apoptosis

Signal transducer and activator of transcription 3 (Stat3) and Myocardin regulate cardiomyocyte differentiation, proliferation, and apoptosis. We report a novel aspect of the cellular function of Myocardin and Stat3 in the regulation of cardiomyocyte apoptosis. Myocardin and Stat3 showed anti-apoptotic function by increasing the expression of Bcl-2 while reducing expression of the pro-apoptotic genes Bax, Apaf-1, caspase-9, and caspase-3. Moreover, myocardin/Stat3-mediated activation of Bcl-2 and Mcl-1 transcription is contingent on the CArG box. Myocardin and Stat3 synergistically inhibited staurosporine-induced cardiomyocyte apoptosis by up-regulating expression of anti-apoptotic Bcl-2 and Mcl-1 in neonatal rat cardiomyocytes. These results describe a novel anti-apoptotic Myocardin/Stat3 signaling pathway operating during cardiomyocyte apoptosis. This provides a molecular explanation for cardiomyocyte apoptosis inhibition as a critical component of myocardial protection.

PKM2 promotes glucose metabolism through a let-7a-5p/Stat3/hnRNP-A1 regulatory feedback loop in breast cancer cells: YAO et al.

Tumor cells metabolize more glucose to lactate in aerobic or hypoxic conditions than normal cells. Pyruvate kinase isoenzyme type M2 (PKM2) is crucial for tumor cell aerobic glycolysis. We established a role for let‐7a‐5p/Stat3/hnRNP‐A1/PKM2 signaling in breast cancer cell glucose metabolism. PKM2 depletion via small interfering RNA (siRNA) inhibits cell proliferation and aerobic glycolysis in breast cancer cells. Signal transducer and activator of transcription 3 (Stat3) promotes upregulation of heterogeneous nuclear ribonucleoprotein (hnRNP)‐A1 expression, hnRNP‐A1 binding to pyruvate kinase isoenzyme (PKM) pre messenger RNA, and the subsequent formation of PKM2. This pathway is downregulated by the microRNA let‐7a‐5p, which functionally targets Stat3, whereas hnRNP‐A1 blocks the biogenesis of let‐7a‐5p to counteract its ability to downregulate the Stat3/hnRNP‐A1/PKM2 signaling pathway. The downregulation of Stat3/hnRNP‐A1/PKM2 by let‐7a‐5p is verified using a breast cancer. These results suggest that let‐7a‐5p, Stat3, and hnRNP‐A1 form a feedback loop, thereby regulating PKM2 expression to modulate glucose metabolism of breast cancer cells. These findings elucidate a new pathway mediating aerobic glycolysis in breast cancers and provide an attractive potential target for breast cancer therapeutic intervention.

Long noncoding RNA H19 competitively binds miR-93-5p to regulate STAT3 expression in breast cancer: LI et al.

The long noncoding RNA H19 is overexpressed in many cancers and acts as an oncogene. Here, we explored the role of H19 in breast cancer cells, including the effect of H19 on proliferation, migration, and invasion of breast cancer cells. We also investigated the relation of H19 to microRNA miR‐93‐5p and signal transducers and activators of transcription 3 (STAT3), the target gene of miR‐93‐5p. Ectopic expression of H19 in MCF‐7 cells and knockdown of H19 in MDA‐MB‐231 cells showed that overexpression of H19 promoted proliferation, migration, and invasion, whereas knockdown of H19 reduced proliferation, migration, and invasion in vitro. Dual‐luciferase reporter assays and RNA‐binding protein immunoprecipitation assays proved that H19 was a target of miR‐93‐5p. In addition, H19 antagonized the downregulation of miR‐93‐5p on its target STAT3 and antagonized miR‐93‐5p‐mediated cell proliferation. Our study revealed a new network in the expression of STAT3 involving H19 and miR‐93‐5p, which may contribute to a better understanding of breast cancer pathogenesis and provide new insights into the treatment of this disease.

Hyperoside and let-7a-5p synergistically inhibits lung cancer cell proliferation via inducing G1/S phase arrest

Lung cancer remains one of the most aggressive human malignancies with a low survival rate. Hyperoside (quercetin-3-O-β-d-galactopyranoside) is a flavonol glycoside with an anti-cancer activity. The microRNA-let-7 was widely regarded as a tumor suppressor in human tumors. Here, we investigated the role of hyperoside and let-7a-5p on the lung cancer cell proliferation, cell cycle and apoptosis in A549 cells in vitro. Our results showed that hyperoside could inhibit the proliferation of A549 cells through inducing apoptosis and G1/S phase arrest. Let-7a-5p could inhibit the proliferation of A549 cells via inhibiting the process of G1/S phase. Additionally, hyperoside and let-7a-5p had a synergetic effect on suppressing the proliferation of A549 cells; microRNA-let-7a-5p directly regulated the expression of CCND1 in A549 cells. Our study illustrated that hyperoside and microRNA-let7a-5p might provide a synergistic effect on anti-cancer, which may provide a new idea for lung cancer treatment.