Suppression of the Growth and Invasion of Human Head and Neck Squamous Cell Carcinomas via Regulating STAT3 Signaling and the miR-21/β-catenin Axis with HJC0152

Wang, Yu; Wang, Sinan; Wu, Yi‐Long; Ren, Yu; Li, Zhaoqing; Yao, Xiaofeng; Zhang, Chao; Ye, Na; Jing, Chao; Dong, Jianwen; Zhang, Kailiang; Sun, Shanshan; Zhao, Minghui; Guo, Wenyu; Qu, Xin; Qiao, Yunfeng; Chen, Haiying; Kong, Linhgping; Jin, Rui; Wang, Xudong; Zhang, Lun; Zhou, Jia; Shen, Qiang; Zhou, Xuan

doi:10.1158/1535-7163.mct-16-0606

Cited by 44 publications

(34 citation statements)

References 51 publications

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“…Our previous studies and a report from other groups have shown that STAT3 is a primary target of HJC0152 in breast cancer, head and neck squamous cell carcinoma, glioma, and gastric cancer . In this study, we showed that STAT3 expression is a prognostic factor for NSCLC patients (Figure A‐C), and that STAT3 is activated in NSCLC cells (Figure D and E).…”

Section: Resultssupporting

confidence: 74%

“…The lysates were then centrifuged (13 000 × g , 4°C) for 15 minutes to obtain total protein lysates. Protein expression was analysed using Western blotting as described previously . The expression level of GAPDH was used as the loading control.…”

Section: Methodsmentioning

confidence: 99%

“…It also has stronger STAT3-inhibiting activity than niclosamide. 19,20 However, little is known about whether HJC0152 has anti-lung cancer activity, and particularly whether it has effects against NSCLC. In this study, we investigated the anti-cancer effect of HJC0152 on human NSCLC cell lines in vitro and NSCLC xenograft tumours in vivo.…”

Section: Introductionmentioning

confidence: 99%

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HJC0152 suppresses human non–small‐cell lung cancer by inhibiting STAT3 and modulating metabolism

et al. 2020

Cell Proliferation

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Objectives Signal transducer and activator of transcription 3 (STAT3) is constitutively activated and overexpressed in many cancers, including non–small‐cell lung cancer (NSCLC). We recently developed HJC0152 as an orally active STAT3 inhibitor. This study focused on investigating HJC0152's effect and mechanism of action in NSCLC. Materials and methods We analysed cell proliferation by MTT assays, cell migration by wound healing and transwell assays, protein levels by Western blot, and apoptosis and reactive oxygen species (ROS) level by flow cytometry. A nude mouse tumorigenesis model was established for in vivo experiment. UHPLC‐QTOF/MS was used for untargeted metabolomic relative quantitation analysis. Results We found that HJC0152 exhibited activity against human NSCLC cells in vitro and NSCLC xenograft tumours in vivo via regulating STAT3 signalling and metabolism. HJC0152 efficiently reduced NSCLC cell proliferation, promoted ROS generation, induced apoptosis, triggered DNA damage and reduced motility in A549 and H460 NSCLC cells. Moreover, HJC0152 significantly inhibited the growth of A549 xenograft tumours in vivo. HJC0152 also affected metabolism, significantly decreasing and perturbating levels of several metabolites in the purine, glutathione and pyrimidine metabolism pathways. Conclusions HJC0152 reduces cellular capacity to scavenge free radicals, leading to ROS generation and accumulation and apoptosis. This study provides a rationale for further developing HJC0152 as a potential therapy for NSCLC and provides insights into the mechanisms by which HJC0152 exerts its anti‐cancer effects.

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Section: Resultssupporting

confidence: 74%

Section: Methodsmentioning

confidence: 99%

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HJC0152 suppresses human non–small‐cell lung cancer by inhibiting STAT3 and modulating metabolism

et al. 2020

Cell Proliferation

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“…Their data suggested that the activation of Nanog/STAT3 signaling participated in this miR-21 production. In conformity with this result, it has been shown that inhibition of nuclear translocation of phosphorylated STAT3 abrogated the downstream miR-21/β-catenin axis, leading to suppression of tumor growth and invasion in HNSCC [59].…”

Section: Microrna-21supporting

confidence: 57%

MicroRNAs as Theranostics Targets in Oral Carcinoma Stem Cells

Hsieh

Liao

Pichler

et al. 2020

Cancers

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Oral cancer belongs to head and neck squamous cell carcinoma and has been recognized as one of the most prevalent malignancies worldwide. Recent studies have suggested that cancer stem cells (CSCs) may participate in tumor initiation, metastasis and even recurrence, so the regulation of CSCs has drawn significant attention over the past decade. Among various molecules that are associated with CSCs, non-coding RNAs (ncRNAs) have been indicated as key players in the acquisition and maintenance of cancer stemness. In addition, accumulating studies have shown that the aberrant expression of these ncRNAs may serve as surrogate diagnostic markers or even therapeutic targets for cancer treatment. The current study reviews the previous work by us and others to summarize how these ncRNAs affect oral cancer stemness and their potential theranostic applications. A better understanding of the implication of these ncRNAs in oral tumorigenesis will facilitate the translation of basic ncRNA research into clinical application in the future.

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“…CAFs have also been shown to enhance the metastatic potential of lung cancers via IL-6/STAT3 signalling pathways [40]. Importantly, studies associated with STAT3 also showed its involvement in enhancing the tumor growth and metastasis of human head and neck squamous cell carcinoma (HNSCC) [41]. In agreement, as described in Supplementary Figure S1, when STAT3 was silenced, CAL27 and SCC-15 cells lost a significant degree of ability to generate tumor spheres and the EVs released from STAT3-silenced tumor spheres, contained a lower level of β-catenin, TGFβ1 and miR-21-5p; these observations strongly suggest that inhibiting signaling networks such as STAT3/β-catenin, associated with the generation of cancer stem cells, could lead to the reduced oncogenic cargos released into the TME.…”

Section: Discussionmentioning

confidence: 99%

Ovatodiolide Suppresses Oral Cancer Malignancy by Down-Regulating Exosomal Mir-21/STAT3/β-Catenin Cargo and Preventing Oncogenic Transformation of Normal Gingival Fibroblasts

Chen

Bamodu

et al. 2019

Cancers

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Oral squamous cell carcinoma (OSCC) is among the most commonly diagnosed malignancies in the world. Patients with OSCC often develop treatment resistance, resulting in a poor prognosis. Mounting evidence indicates that interactions between cancerous cells and other components of the tumor microenvironment (TME) determine their response to treatment. Herein, we examined the role of cancer stem cell-derived extracellular vesicles (CSC_EVs) generated from CAL27 and SCC-15 OSCC cells in the development of cisplatin (CDDP) resistance. We demonstrated that CSC_EVs enhance CDDP resistance, clonogenicity, and the tumorsphere formation potential of OSCC cells. Our bioinformatics analyses revealed that OSCC_EVs are enriched with microRNA (miR)-21-5p and are associated with increased metastasis, stemness, chemoresistance, and poor survival in patients with OSCC. Mechanistically, enhanced activity of CSC_EVs was positively correlated with upregulated Cancers 2020, 12, 56 2 of 16 β-catenin, phosphatidylinositol-3 kinase (PI3K), signal transducer and activator of transcription 3 (STAT3), mammalian target of rapamycin (mTOR), and transforming growth factor (TGF)-β1 messenger (m)RNA and protein expression levels. CSC_EVs also conferred a cancer-associated fibroblast (CAF) phenotype on normal gingival fibroblasts (NGFs), with the resultant CAFs enhancing the oncogenicity of OSCC cells. Interestingly, treatment with ovatodiolide (OV), the bioactive component of Anisomeles indica, suppressed OSCC tumorigenesis by reducing the cargo content of EVs derived from CSCs, suppressing self-renewal, and inhibiting the NGF-CAF transformation by disrupting EV-TME interactions. Moreover, by suppressing miR-21-5p, STAT3, and mTOR expressions in CSC_EVs, OV re-sensitized CSCs to CDDP and suppressed OSCC tumorigenesis. In vivo, treatment with OV alone or in combination with CDDP significantly reduced the tumor sphere-forming ability and decreased EV cargos containing mTOR, PI3K, STAT3, β-catenin, and miR-21-5p. In summary, our findings provide further strong evidence of OV's therapeutic effect in OSCC.

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Suppression of the Growth and Invasion of Human Head and Neck Squamous Cell Carcinomas via Regulating STAT3 Signaling and the miR-21/β-catenin Axis with HJC0152

Cited by 44 publications

References 51 publications

HJC0152 suppresses human non–small‐cell lung cancer by inhibiting STAT3 and modulating metabolism

HJC0152 suppresses human non–small‐cell lung cancer by inhibiting STAT3 and modulating metabolism

MicroRNAs as Theranostics Targets in Oral Carcinoma Stem Cells

Ovatodiolide Suppresses Oral Cancer Malignancy by Down-Regulating Exosomal Mir-21/STAT3/β-Catenin Cargo and Preventing Oncogenic Transformation of Normal Gingival Fibroblasts

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