RUNX1/EGFR pathway contributes to STAT3 activation and tumor growth caused by hyperactivated mTORC1

Lin, Wei; Wan, Xiaofeng; Sun, Anjiang; Zhou, Meng; Xu, Chen; Li, Yanling; Wang, Zixi; Huang, Hailiang; Li, Hongwu; Chen, Xianguo; Hua, Juan; Zha, Xiaojun

doi:10.1016/j.omto.2021.10.009

Cited by 13 publications

(12 citation statements)

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“…Thus, our study illustrated a feedback loop between STAT3 and MBNL1 downstream of mTORC1 signaling and provided the first evidence that mTORC1 activates STAT3, at least in part, by MBNL1 inhibition. Together with our previous findings that mTORC1 upregulates STAT3 protein levels through miR-125b-5p suppression and mTORC1 activates STAT3 under the promotion of EGFR expression [ 25 , 32 ], our results open a possibility that multiple molecular mechanisms are involved in mTORC1-dependent regulation of STAT3. However, it remains to be verified how MBNL1 regulates the activity of STAT3.…”

Section: Discussionsupporting

confidence: 87%

“…4 A and Supplementary Table S 7 ). To further screen target genes, the Venn analysis of these predicted target genes with downregulated differentially expressed genes in Tsc2 − / − MEFs as compared with Tsc2 + / + MEFs and decreased differentially expressed genes in angiofibroma (AF) of TSC patients vs. normal skin obtained only one candidate, MBNL1 [ 32 , 33 ] (Fig. 4 B, Supplementary Tables S 8 and S 9 ).…”

Section: Resultsmentioning

confidence: 99%

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STAT3/miR-130b-3p/MBNL1 feedback loop regulated by mTORC1 signaling promotes angiogenesis and tumor growth

Liu

et al. 2022

J Exp Clin Cancer Res

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Background Aberrantly activated mammalian target of rapamycin complex 1 (mTORC1) plays a vital role in tumor angiogenesis, but its precise mechanisms are still unclear. Methods Micro-RNA-130b-3p (miR-130b-3p) expression in mTORC1-activated and control cells was examined by quantitative real-time PCR (qRT-PCR). MiR-130b-3p levels and their correlation with mTORC1 activity were evaluated by analyzing publicly available databases and in-house head and neck squamous cell carcinoma (HNSCC) tissues. The role of miR-130b-3p in mTORC1-mediated angiogenesis and tumor growth was examined using tube formation assay, chicken chorioallantoic membrane assay, cell line − derived xenograft models, and an HNSCC patient-derived xenograft (PDX) model. The regulatory mechanisms among signal transducer and activator of transcription 3 (STAT3), miR-130b-3p, and muscleblind-like protein 1 (MBNL1) were investigated via bioinformatics analyses, qRT-PCR, western blot, RNA immunoprecipitation, immunofluorescence, luciferase reporter assay, and chromatin immunoprecipitation assay. Results Elevated miR-130b-3p enhanced the angiogenic and tumorigenic abilities of mTORC1-activated cells both in vitro and in vivo. STAT3, a downstream effector of mTORC1, transactivated miR-130b-3p by direct binding promoter of the miR-130b gene. MBNL1 was identified as a direct target of miR-130b-3p. MBNL1 depletion rescued the compromised angiogenesis and tumor growth caused by miR-130b-3p inhibition. MiR-130b-3p levels were significantly upregulated and positively correlated with mTORC1 signaling in multiple cancers. MiR-130b-3p inhibition attenuated tumor angiogenesis and growth in an HNSCC PDX model. MBNL1 feedback inhibited STAT3 activation in mTORC1-activated cells. Conclusions The STAT3/miR-130b-3p/MBNL1 feedback loop plays a vital role in mTORC1-mediated angiogenesis and tumor progression. This pathway could be targeted for therapeutic intervention of mTORC1-related cancers.

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Section: Discussionsupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

STAT3/miR-130b-3p/MBNL1 feedback loop regulated by mTORC1 signaling promotes angiogenesis and tumor growth

Liu

et al. 2022

J Exp Clin Cancer Res

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“…Although phosphorylation of STAT-3 was observed in non-tumorigenic RWPE-1 cells, this may be mediated by EGF ( 50 ). This growth factor is necessary for maintenance and proliferation of RWPE-1 cells in culture ( 51 ).…”

Section: Discussionmentioning

confidence: 99%

Dual STAT‑3 and IL‑6R inhibition with stattic and tocilizumab decreases migration, invasion and proliferation of prostate cancer cells by targeting the IL‑6/IL‑6R/STAT‑3 axis

et al. 2022

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Prostate cancer (PCa) is a key public health problem worldwide; at diagnosis, a high percentage of patients exhibit tumor cell invasion of adjacent tissue. STAT-3, IL-6 receptor (R) and IL-6 serum levels are associated with enhanced PCa migratory, invasive, clonogenic and metastatic ability. Inhibiting the STAT-3 pathway at different levels (cytokines, receptors, and kinases) exhibits relative success in cancer. The present study investigated the effect of Stattic (Stt) + Tocilizumab (Tcz) on proliferative, clonogenic, migratory and invasive ability of human metastatic PCa (assessed by colony formation, wound healing and migration assay). RWPE-1 (epithelial prostate immortalized cells), 22Rv1 (Tumor cells), LNCaP (Metastatic cells) and DU-145 (metastatic, castration-resistant prostate cells) cells were used in vitro to evaluate levels of cytokines, chemokines, growth factors (Cytometric Bead Array), STAT-3, phosphorylated STAT-3 (In-Cell Western), IL-6R, vimentin and epithelial (E-) cadherin (Western Blot). The effect of inhibition of STAT-3 (expressed constitutively in DU-145 cells) with Stt and/or Tcz on expression levels of vimentin, VEGF, and E-cadherin, as well as proliferative, clonogenic, migratory and invasive capacity of metastatic PCa cells was assessed. The expression levels of IL-6, C-X-C chemokine ligand 8, VEGF and vimentin, as well as proliferation and migration, were increased in metastatic PCa cells. Treatment with Stt or Tcz decreased vimentin and VEGF and increased E-cadherin expression levels and inhibited proliferative, clonogenic, migratory and invasive capacity of DU-145 cells; addition of IL-6 decreased this inhibitory effect. However, Stt + Tcz maintained inhibition even in the present of high concentrations of IL-6. Stt + Tcz decreased expression of vimentin and VEGF and inhibited the proliferative, clonogenic, migratory and invasive capacity of metastatic PCa cells. To the best of our knowledge, the present study is the first to combine Stt, a STAT-3 inhibitor, with Tcz, an antibody against IL-6R, to target tumor cells.

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“…RNA isolation and purification were performed using TRIzol RNA. The Complementary DNA Synthesis SuperMix Kit (ThermoFisher Scientific) was used to synthesize complementary DNA, which was subjected to qRT-PCR using SYBR ® Premix Ex TaqTM II (TaKaRa) and the Real-Time System ( Lin et al, 2021 ) (Roche Life Science). The gene expression levels were normalized to GAPDH messenger RNA (mRNA) expression.…”

Section: Methodsmentioning

confidence: 99%

Identification and validation of a novel tumor driver gene signature for diagnosis and prognosis of head and neck squamous cell carcinoma

Liu

Liu²,

Ding³

et al. 2022

Front. Mol. Biosci.

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Objective: Head and neck squamous cell carcinoma (HNSCC) is a common heterogeneous cancer with complex carcinogenic factors. However, the current TNM staging criteria to judge its severity to formulate treatment plans and evaluate the prognosis are particularly weak. Therefore, a robust diagnostic model capable of accurately diagnosing and predicting HNSCC should be established.Methods: Gene expression and clinical data were retrieved from The Cancer Genome Atlas and Gene Expression Omnibus databases. Key prognostic genes associated with HNSCC were screened with the weighted gene co-expression network analysis and least absolute shrinkage and selection operator (LASSO) Cox regression model analysis. We used the timeROC and survival R packages to conduct time-dependent receiver operating characteristic curve analyses and calculated the area under the curve at different time points of model prediction. Patients in the training and validation groups were divided into high- and low-risk subgroups, and Kaplan-Meier (K-M) survival curves were plotted for all subgroups. Subsequently, LASSO and support vector machine algorithms were used to screen genes to construct diagnostic model. Furthermore, we used the Wilcoxon signed-rank test to compare the half-maximal inhibitory concentrations of common chemotherapy drugs among patients in different risk groups. Finally, the expression levels of eight genes were measured using quantitative real-time polymerase chain reaction and immunohistochemistry.Results: Ten genes (SSB, PFKP, NAT10, PCDH9, SHANK2, PAX8, CELSR3, DCLRE1C, MAP2K7, and ODF4) with prognostic potential were identified, and a risk score was derived accordingly. Patients were divided into high- and low-risk groups based on the median risk score. The K-M survival curves confirmed that patients with high scores had significantly worse overall survival. Receiver operating characteristic curves proved that the prognostic signature had good sensitivity and specificity for predicting the prognosis of patients with HNSCC. Univariate and multivariate Cox regression analyses confirmed that the gene signature was an independent prognostic risk factor for HNSCC. Diagnostic model was built by identifying eight genes (SSB, PFKP, NAT10, PCDH9, CELSR3, DCLRE1C, MAP2K7, and ODF4). The high-risk group showed higher sensitivity to various common chemotherapeutic drugs. DCLRE1C expression was higher in normal tissues than in HNSCC tissues.Conclusion: Our study identified the important role of tumor-driver genes in HNSCC and their potential clinical diagnostic and prognostic values to facilitate individualized management of patients with HNSCC.

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RUNX1/EGFR pathway contributes to STAT3 activation and tumor growth caused by hyperactivated mTORC1

Cited by 13 publications

References 53 publications

STAT3/miR-130b-3p/MBNL1 feedback loop regulated by mTORC1 signaling promotes angiogenesis and tumor growth

STAT3/miR-130b-3p/MBNL1 feedback loop regulated by mTORC1 signaling promotes angiogenesis and tumor growth

Dual STAT‑3 and IL‑6R inhibition with stattic and tocilizumab decreases migration, invasion and proliferation of prostate cancer cells by targeting the IL‑6/IL‑6R/STAT‑3 axis

Identification and validation of a novel tumor driver gene signature for diagnosis and prognosis of head and neck squamous cell carcinoma

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