STAT3: A Potential Drug Target for Tumor and Inflammation

Hu, Yang; Han, Xu; Liu, Xin Hua

doi:10.2174/1568026619666190620145052

Cited by 52 publications

(34 citation statements)

References 143 publications

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“…In contrast, M2 polarization, associated with immune suppression and tumor progression, is induced by STAT3 and STAT6 activation [38]. Interestingly, we found that although inducing M2 macrophage polarization, Mifamurtide exerts a concomitant inhibition of the STAT3 pathway, constitutively activated in OS, reducing STAT3 phosphorylation [39]. The mTOR signaling pathway has been recently implicated in regulating macrophage polarization [40].…”

Section: Discussionmentioning

confidence: 69%

Mifamurtide and TAM-like macrophages: effect on proliferation, migration and differentiation of osteosarcoma cells

et al. 2020

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Tumor-associated macrophages and their alternative activation states together with cytokines and growth factors trapped in tumor microenvironment contribute to the progression of OS. In contrast to other tumor types, M2 polarized macrophages, reduce metastasis and improve survival in osteosarcoma patients. Mifamurtide is an immunomodulatory drug given together with standard adjuvant chemotherapy in high-grade osteosarcoma to improve outcome. Macrophages obtained from peripheral blood mononucleated cells of healthy donors and MG63 cells were cultured alone and together, and treated with Mifamurtide. We analyzed the effects of Mifamurtide on macrophage polarization and on MG63 proliferation, migration and differentiation, evaluating the expression of M1/M2 and osteoblast markers and molecules involved in metastasis and proliferation pathways. Our data suggest that Mifamurtide, switching macrophage polarization towards a TAM-like intermediate M1/M2 phenotype, may modulate the delicate balance between pro-inflammatory and immunomodulatory macrophage functions. Moreover, Mifamurtide may inhibit the cellular proliferation and induce the tumor cell differentiation, probably through the down regulation of pSTAT3, pAKT and IL-17R.

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Section: Discussionmentioning

confidence: 69%

Mifamurtide and TAM-like macrophages: effect on proliferation, migration and differentiation of osteosarcoma cells

et al. 2020

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“…A previous study reported the role of IL-6/JAK2/STAT3 in nonsmall-cell lung cancer cell proliferation and migration through microvascular proliferation [21]. Other studies have validated this and have identified the pathways regulating the process [18][19][20][21][22][23]. Proinflammatory cytokine interleukin-6 (IL-6) released from inflammatory cells binds to IL-6 receptor α and active gp130 to induce the phosphorylation of JAK2 (P-JAK2), in response to hypoxia [24][25][26][27].…”

Section: Introductionmentioning

confidence: 77%

“…e Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway plays a vital role in mediating angiogenesis against ischemic injury [11][12][13][14][15][16][17]. Importantly, JAK2/STAT3 signaling has been specifically shown to protect against cerebral ischemia-reperfusion injury by inducing microvessel proliferation [18][19][20][21][22][23]. A previous study reported the role of IL-6/JAK2/STAT3 in nonsmall-cell lung cancer cell proliferation and migration through microvascular proliferation [21].…”

Section: Introductionmentioning

confidence: 99%

Chronic Hypoxia-Induced Microvessel Proliferation and Basal Membrane Degradation in the Bone Marrow of Rats Regulated through the IL-6/JAK2/STAT3/MMP-9 Pathway

Zhu

Yang

et al. 2020

BioMed Research International

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Chronic hypoxia (CH) is characterized by long-term hypoxia that is associated with microvessel proliferation and basal membrane (BM) degradation in tissues. The IL-6/JAK2/STAT3/MMP-9 pathway has been described in a variety of human cancers and plays an essential role in microvessel proliferation and BM degradation. Therefore, this study investigated the role of the IL-6/JAK2/STAT3/MMP-9 pathway in hypoxia-mediated microvessel proliferation and BM degradation in the rat bone marrow. Eighty pathogen-free Sprague Dawley male rats were randomly divided into four groups (20 per group)—control group, CH group (exposed to hypoxia in a hypobaric chamber at a simulated altitude of 5000 m for 28 d), CH + STAT3 inhibitor group (7.5 mg/kg/d), and CH + DMSO group. Microvessel density (MVD) and BM degradation in the bone marrow were determined by immunofluorescence staining and transmission electron microscopy. Serum IL-6 levels were assessed by enzyme-linked immunosorbent assay (ELISA), and the levels of P-JAK2, P-STAT3, and MMP-9 were assessed by western blot analysis and real-time reverse transcription PCR (RT-PCR). Hypoxia increased serum IL-6 levels, which in turn increased JAK2 and STAT3 phosphorylation, which subsequently upregulated MMP-9. Overexpression of MMP-9 significantly promoted the elevation of MVD and BM degradation. Inhibition of STAT3 using an inhibitor, SH-4-54, significantly downregulated MMP-9 expression and decreased MVD and BM degradation. Surprisingly, STAT3 inhibition also decreased serum IL-6 levels and JAK2 phosphorylation. Our results suggest that the IL-6/JAK2/STAT3/MMP-9 pathway might be related to CH-induced microvessel proliferation and BM degradation in the bone marrow.

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“…STAT3 is also involved in many diseases, such as airway in ammation and rheumatoid arthritis [32][33][34][35]. The persistent activation and high expression of STAT3 in tumour cells promotes tumour growth and proliferation [7]. And sustained activation of STAT3 also mediates tumour-promoting in ammation [36].…”

Section: Discussionmentioning

confidence: 99%

“…STAT3 is a cellular signal transcription factor involved in the regulation of many cellular activities [7]. STAT3 may regulate the differentiation of CD4 + T cells into Th17 cells [8].…”

mentioning

confidence: 99%

The intervention of S1PR1/STAT3 signaling pathway by inhibiting the expression of STAT3 attenuates the valvular damage due to rheumatic heart disease

Xian¹,

Chen²,

Yi-ming³

et al. 2020

Preprint

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Background Rheumatic heart disease (RHD) is a social health problem that affects many patients every year, but its pathogenesis is still unclear. Recent studies have found that the sphingosine 1-phosphate receptor 1 (S1PR1)/signal transducer and activator of transcription 3 (STAT3) signaling pathway is activated during the development of valvular damage caused by RHD. STAT3 plays an important role in the differentiation of CD4 + T cells into T helper 17 (Th17) cells, and Th17 cell-related cytokines are involved in the development of RHD. In this work, we investigated whether altering the S1PR1/STAT3 signaling pathway by inhibiting the expression of STAT3 attenuates valvular damage due to RHD. Methods Inactivated Group A streptococci (GAS) and complete Freund’s adjuvant (CFA) were used to establish the RHD rat model. STAT3-small interfering RNA (STAT3-siRNA) was used to directly inhibit the expression of STAT3 in the heart. Histological examination was used to evaluate the degree of inflammation and fibrosis in valve tissues. Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry were used to detect the levels of interleukin (IL)-6 and IL-17 in serum and valve tissue. Reverse transcription-quantitative PCR (RT-qPCR) was used to detect the mRNA expression of S1PR1 and STAT3. Western blotting (WB) and immunohistochemistry were used to detect the protein expression of S1PR1, STAT3, phosphorylated (p-) STAT3, retinoic acid-related orphan receptor gamma T (RORγt). Results The expression of S1PR1 in valve tissues of RHD model rats was decreased. The degree of valvular inflammation and fibrosis of RHD model rats was increased. The levels of IL-6 and IL-17 in valves and serum of RHD model rats were increased as well as an increase of p-STAT3 in valve tissues. Inhibition of STAT3 by STAT3-siRNA decreased STAT3 expression and reduced the total amount of p-STAT3, resulting in decreased expression of IL-6, IL-17 and RORγt in valves and serum and reduced valvular inflammatory response and fibrosis. Conclusions These results suggest that inhibiting the expression of STAT3 in the heart may reduce the valvular damage caused by rheumatic heart disease.

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STAT3: A Potential Drug Target for Tumor and Inflammation

Cited by 52 publications

References 143 publications

Mifamurtide and TAM-like macrophages: effect on proliferation, migration and differentiation of osteosarcoma cells

Mifamurtide and TAM-like macrophages: effect on proliferation, migration and differentiation of osteosarcoma cells

Chronic Hypoxia-Induced Microvessel Proliferation and Basal Membrane Degradation in the Bone Marrow of Rats Regulated through the IL-6/JAK2/STAT3/MMP-9 Pathway

The intervention of S1PR1/STAT3 signaling pathway by inhibiting the expression of STAT3 attenuates the valvular damage due to rheumatic heart disease

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