scholarly journals ALKBH5-HOXA10 loop-mediated JAK2 m6A demethylation and platinum resistance in epithelial ovarian cancer

2021 ◽  
Author(s):  
Sipei Nie ◽  
Lin Zhang ◽  
Jinhui Liu ◽  
Yicong Wan ◽  
Yi Jiang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Signaling Pathway ◽  
Platinum Resistance ◽  
Rna Seq ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Rna Immunoprecipitation

Abstract Background: Chemotherapy resistance remains a barrier in improving the prognosis of epithelial ovarian cancer (EOC), but its mechanism remains to be elucidated. ALKBH5 has been recently proven to be an RNA N6-methyladenosine (m6A) demethyltransferase associated with various cancers, but its role in cancer therapeutic resistance remains unclear. This study aimed to investigate the role of AlkB homolog 5 (ALKBH5) in platinum-resistant EOC.Methods: Functional assays were performed both in vitro and in vivo. RNA sequencing (RNA-seq), m6A-modified RNA immunoprecipitation sequencing (MeRIP-seq), chromatin immunoprecipitation, RNA immunoprecipitation, and luciferase reporter and actinomycin-D assays were performed to investigate RNA/RNA interaction and m6A modification of the ALKBH5-HOXA10 loop.Results: ALKBH5 was upregulated in platinum-resistant EOC and promoted cancer cell cisplatin resistance both in vivo and in vitro. Notably, HOXA10 was found to be the upstream transcription factor of ALKBH5 and formed a loop with ALKBH5., and its overexpression facilitated EOC cell chemoresistance both in vivo and in vitro. HOXA10 overexpression was found to facilitate EOC cell chemoresistance both in vivo and in vitro. Collective results of MeRIP-seq and RNA-seq showed that JAK2 is an m6A-modified gene targeted by ALKBH5. The JAK2/STAT3 signaling pathway was activated by overexpression of the ALKBH5-HOXA10 loop, and this resulted in EOC chemoresistance. Cell sensitivity to cisplatin was rescued by ALKBH5 and HOXA10 knockdown or inhibition of the JAK2/STAT3 signaling pathway in EOC cells overexpressing ALKBH5-HOXA10.Conclusions: The ALKBH5-HOXA10 loop jointly activates the JAK2/STAT3 signaling pathway by mediating JAK2 m6A demethylation, promoting EOC resistance to platinum. Thus, inhibition of the expression of the ALKBH5-HOXA10 loop maybe a potential strategy to overcome platinum resistance in EOC.

scholarly journals ALKBH5-HOXA10 loop-mediated JAK2 m6A demethylation and cisplatin resistance in epithelial ovarian cancer

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Sipei Nie ◽  
Lin Zhang ◽  
Jinhui Liu ◽  
Yicong Wan ◽  
Yi Jiang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Signaling Pathway ◽  
Cisplatin Resistance ◽  
Rna Seq ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Rna Immunoprecipitation

Abstract Background Chemotherapy resistance remains a barrier to improving the prognosis of epithelial ovarian cancer (EOC). ALKBH5 has recently been shown to be one of the RNA N6-methyladenosine (m6A) demethyltransferases associated with various cancers, but its role in cancer therapeutic resistance remains unclear. This study aimed to investigate the role of AlkB homolog 5 (ALKBH5) in cisplatin-resistant EOC. Methods Functional assays were performed both in vitro and in vivo. RNA sequencing (RNA-seq), m6A-modified RNA immunoprecipitation sequencing (MeRIP-seq), chromatin immunoprecipitation, RNA immunoprecipitation, and luciferase reporter and actinomycin-D assays were performed to investigate RNA/RNA interaction and m6A modification of the ALKBH5-HOXA10 loop. Results ALKBH5 was upregulated in cisplatin-resistant EOC and promoted cancer cell cisplatin resistance both in vivo and in vitro. Notably, HOXA10 formed a loop with ALKBH5 and was found to be the upstream transcription factor of ALKBH5. HOXA10 overexpression also facilitated EOC cell chemoresistance both in vivo and in vitro. Collective results of MeRIP-seq and RNA-seq showed that JAK2 is the m6A-modified gene targeted by ALKBH5. The JAK2/STAT3 signaling pathway was activated by overexpression of the ALKBH5-HOXA10 loop, resulting in EOC chemoresistance. Cell sensitivity to cisplatin was rescued by ALKBH5 and HOXA10 knockdown or inhibition of the JAK2/STAT3 signaling pathway in EOC cells overexpressing ALKBH5-HOXA10. Conclusions The ALKBH5-HOXA10 loop jointly activates the JAK2/STAT3 signaling pathway by mediating JAK2 m6A demethylation, promoting EOC resistance to cisplatin. Thus, inhibition of the expression of the ALKBH5-HOXA10 loop may be a potential strategy to overcome cisplatin resistance in EOC.

scholarly journals Dynasore suppresses cell proliferation, migration, and invasion and enhances the antitumor capacity of cisplatin via STAT3 pathway in osteosarcoma

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Binlong Zhong ◽  
Deyao Shi ◽  
Fashuai Wu ◽  
Shangyu Wang ◽  
Hongzhi Hu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Signaling Pathway ◽  
Mapk Pathway ◽  
Migration And Invasion ◽  
G1 Arrest ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Candidate Drug

Abstract Osteosarcoma (OS) is the most common malignant bone tumor. The prognosis of metastatic and recurrent OS patients still remains unsatisfactory. Cisplatin reveals undeniable anti-tumor effect while induces severe side effects that threatening patients’ health. Dynasore, a cell-permeable small molecule that inhibits dynamin activity, has been widely studied in endocytosis and phagocytosis. However, the anti-tumor effect of dynasore on OS has not yet been ascertained. In the present study, we suggested that dynasore inhibited cell proliferation, migration, invasion, and induced G0/G1 arrest of OS cells. Besides, dynasore repressed tumorigenesis of OS in xenograft mouse model. In addition, we demonstrated that dynasore improved the anti-tumor effect of cisplatin in vitro and in vivo without inducing nephrotoxicity and hepatotoxicity. Mechanistically, dynasore repressed the expression of CCND1, CDK4, p-Rb, and MMP-2. Furthermore, we found that dynasore exerts anti-tumor effects in OS partially via inhibiting STAT3 signaling pathway but not ERK-MAPK, PI3K-Akt or SAPK/JNK pathways. P38 MAPK pathway served as a negative regulatory mechanism in dynasore induced anti-OS effects. Taken together, our study indicated that dynasore does suppress cell proliferation, migration, and invasion via STAT3 signaling pathway, and enhances the antitumor capacity of cisplatin in OS. Our results suggest that dynasore is a novel candidate drug to inhibit the tumor growth of OS and enhance the anti-tumor effects of cisplatin.

scholarly journals Escin Sodium Improves the Prognosis of Acute Pancreatitis via Promoting Cell Apoptosis by Suppression of the ERK/STAT3 Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-26
Author(s):  
Qian Zhang ◽  
Chen Zhao ◽  
Lei Zhang ◽  
Kai Sun ◽  
Linlin Yu ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Signaling Pathway ◽  
Cell Apoptosis ◽  
Inflammatory Responses ◽  
Horse Chestnut ◽  
Inflammatory Disorder ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

Acute pancreatitis (AP), an inflammatory disorder of the pancreas, can cause systemic inflammatory responses. Escin Sodium (ES), a natural mixture of triterpene saponins extracted from the dry ripe fruit of Fructus Aesculi or horse chestnut crude, has been demonstrated to have antiedematous, anti-inflammatory, and antiexudative effects. We here aim to investigate the effects of ES pretreatment on AP in vivo and in vitro and explore its potential molecular mechanism. In the present study, we demonstrated that ES pretreatment could apparently decrease amylase and lipase, downregulate inflammatory cytokines, and attenuate pancreatic damage. Additionally, the increased expression of apoptotic-related proteins and the results of flow cytometry demonstrated the effects of ES on promoting apoptosis in acinar cells. Moreover, ES could enhance mitochondrial membrane potential (MMP, ΔΨm) and reactive oxygen species (ROS) level and reduce intracellular calcium concentration, which are closely related to mitochondrial-mediated death. The effect of ES pretreatment on acinar cell apoptosis was furtherly confirmed by the regulatory pathway of the ERK/STAT3 axis. These results suggest that ES attenuates the severity of AP by enhancing cell apoptosis via suppressing the ERK/STAT3 signaling pathway. These findings provide evidence for ES which is treated as a novel and potent therapeutic for the treatment of AP.

scholarly journals Chemokine CXCL-2 Regulates Resistance to Platinum in Epithelial Ovarian Cancer by Mediating ATR/CHK1 Signaling Pathway

2020 ◽  
Author(s):  
Sipei Nie ◽  
Yicong Wan ◽  
Hui Wang ◽  
Jinhui Liu ◽  
Jing Yang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Signaling Pathway ◽  
Cancer Cell ◽  
Treatment Strategies ◽  
Cell Cycle Checkpoint ◽  
Platinum Resistance ◽  
Platinum Resistant ◽  
Cell Assays

Abstract Backgrounds：Platinum-resistance remains a challenge to recurrence and metastasis of epithelial ovarian cancer (EOC) and the mechanisms are unidentified. Tumor microenvironment (TME) and chemokine might play a key role in tumor chemoresistance. This study is designed to reveal the important role of CXCL-2 in causing EOC platinum-resistance. Materials and Methods: Differently expressed chemokines were selected based on the GSE114206 dataset of GEO database. Chemokines levels of platinum-sensitive and platinum-resistant EOC. Cell assays were performed and the cell stem characteristics were investigated for exploring the roles of CXCL-2 in EOC chemoresistance. We further explored the downstream signaling pathway regulated by CXCL-2 by detecting the expression of related molecules and rescue assay with the signaling inhibitor.Results: CXCL-2, CXCL-11 and CXCL-13 were found up-regulated in platinum-resistant EOC based on GSE114206 databases, and CXCL-2 was identified as key chemokine by validation. The cell assays showed overexpressing CXCL-2 and co-culturing with recombinant human CXCL-2 promoted cancer cell chemoresistance. Conversely, knocking down CXCL-2 and co-culturing with neutralizing antibody to CXCL-2 reduced cisplatin-resistance in cisplatin-resistant EOC cells. CXCL-2 levels regulated the stemness of cancer cells and activated ataxia telangiectasia and Rad3-related (ATR)/cell cycle checkpoint kinase1 (CHK1) signaling pathway. The cancer cell chemoresistance can be saved by CXCL-2 receptor inhibitor (SB225002) and CHK1 inhibitor (SAR-020106) in vitro. Conclusion: These results identified a CXCL-2 mediated platinum-resistance mechanism in EOC, and provided a novel target for chemoresistance prevention and treatment strategies.

scholarly journals EPDR1, Which Is Negatively Regulated by miR-429, Suppresses Epithelial Ovarian Cancer Progression via PI3K/AKT Signaling Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhendan Zhao ◽  
Zhiling Wang ◽  
Pengling Wang ◽  
Shujie Liu ◽  
Yingwei Li ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Signaling Pathway ◽  
Cancer Progression ◽  
Figo Stage ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Gynecology And Obstetrics

Epithelial ovarian cancer (EOC) is the main pathological type of ovarian cancer. In this study, we found that ependymin-related 1 (EPDR1) was remarkably downregulated in EOC tissues, and low EPDR1 expression was associated with International Federation of Gynecology and Obstetrics (FIGO) stage, metastasis, and poor prognosis. We confirmed that EPDR1 overexpression dramatically suppressed EOC cell proliferation, migration, and invasion in vitro and in vivo. Mechanistically, EPDR1 inhibited EOC tumorigenesis and progression, at least in part, through the repression of the PI3K (Phosphoinositide 3-kinase)/AKT (AKT Serine/Threonine Kinase 1) signaling pathway. Furthermore, the expression and function of EPDR1 were regulated by miR-429, as demonstrated by luciferase reporter assays and rescue experiments. In conclusion, our study validated that EPDR1, negatively regulated by miR-429, played an important role as a tumor-suppressor gene in EOC development via inhibition of the PI3K/AKT pathway. The miR-429/EPDR1 axis might provide novel therapeutic targets for individualized treatment of EOC patients in the future.

scholarly journals Bufalin suppresses tumour microenvironment-mediated angiogenesis by inhibiting the STAT3 signaling pathway

2021 ◽  
Author(s):  
Ke Xu ◽  
Kai Fang ◽  
Yueping Zhan ◽  
Yuqian Wang ◽  
Chengqi Wu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Endothelial Cells ◽  
Tumor Microenvironment ◽  
Signaling Pathway ◽  
Umbilical Vein ◽  
Tumour Microenvironment ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

Abstract Background Anti-angiogenesis therapy has increasingly become an important strategy for the treatment of colorectal cancer. Recent studies have shown that tumor microenvironment (TME) promotes tumour angiogenesis. Bufalin is an active compound whose anti-tumor efficacy has been proven by previous studies. However, there are very few studies on the anti-angiogenic effects of bufalin. Methods Herein, human umbilical vein endothelial cells (HUVEC) tube formation, migration and adhesion test were used to assess angiogenesis in vitro. Western blot and quantitative PCR were used to detect relevant protein levels and the expressions of mRNAs. Subcutaneous xenograft tumor model and hepatic metastasis model in mice were established to investigate the influence of bufalin on angiogenesis-mediated by TME in vivo. Results We found that the angiogenesis mediated by tumor microenvironment cells was significantly inhibited in the present of bufalin. The results demonstrated that the pro-angiogenic gene in HUVEC such as VEGF, PDGFA, E-selectin and P-selectin were downregulated by bufalin, and the downregulation was regulated by inhibiting the STAT3 pathway. Overexpression STAT3 could reverse the inhibitory effect of bufalin on angiogenesis. What is more, few reduction of angiogenesis when bufalin directly acted on tumor microenvironment cells. Conclusion Our findings demonstrate that bufalin suppresses tumour microenvironment-mediated angiogenesis by inhibiting the STAT3 signaling pathway of vascular endothelial cells, which reveals that bufalin may be used as a new anti-angiogenic adjuvant therapy medicine in the treatment of colorectal cancer.

scholarly journals HBD Inhibits the Development of Colitis-Associated Cancer in Mice via the IL-6R/STAT3 Signaling Pathway

2019 ◽  
Vol 20 (5) ◽  
pp. 1069 ◽  
Author(s):  
Song Deng ◽  
Aiping Wang ◽  
Xi Chen ◽  
Qun Du ◽  
Yanli Wu ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Intestinal Inflammation ◽  
Underlying Mechanism ◽  
Peptic Ulcers ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Hct 116 ◽  
Chronic Intestinal Inflammation

Colitis-associated cancer (CAC) is a malignant disease of the colon that is caused by recurrent episodes of chronic intestinal inflammation. Huangqi Baizhu decoction (HBD) is a classic prescription comprised of Radix Astragali and Rhizoma Atractylodis, which are usually used to treat digestive conditions, such as peptic ulcers, colitis, or colorectal carcinoma in clinics. HBD is well known for “tonifying qi and spleen” based on the theories of traditional Chinese medicine, and has the preponderant effect of alleviating chronic intestinal mucosa damage associated with disease. However, the underlying mechanism behind this is still unknown. In the current study, we employed the AOM/DSS mouse model to analyze the effects of HBD on the development of inflammation in colonic carcinoma. The in vivo study showed that HBD could significantly reduce the mortality of mice and control the incidence and size of colonic tumors by inhibiting the IL-6/STAT3 signaling pathway. In vitro, Astragaloside and Atractylenolide (CAA), the main components of HBD, inhibited the proliferation of HCT-116 cells as determined by an MTT assay. Furthermore, CAA notably suppressed the protein expression of IL-6R, STAT3, Survivin, and Cyclin D1 induced by IL-6 in HCT-116 and RAW264.7 cells. These results suggested that HBD exhibits anti-inflammatory and anti-proliferative effects, inhibiting the development of CAC in mice.

scholarly journals Krupple-Like Factor 5 is a Potential Therapeutic Target and Prognostic Marker in Epithelial Ovarian Cancer

2020 ◽  
Vol 11 ◽  
Author(s):  
Abdul K. Siraj ◽  
Poyil Pratheeshkumar ◽  
Sasidharan Padmaja Divya ◽  
Sandeep Kumar Parvathareddy ◽  
Khadija A. Alobaisi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Growth ◽  
Epithelial Ovarian Cancer ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Therapeutic Target ◽  
Potential Therapeutic Target ◽  
Mesenchymal Transition ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy. Despite current therapeutic and surgical options, advanced EOC shows poor prognosis. Identifying novel molecular therapeutic targets is highly needed in the management of EOC. Krupple-like factor 5 (KLF5), a zinc-finger transcriptional factor, is highly expressed in a variety of cancer types. However, its role and expression in EOC is not fully illustrated. Immunohistochemical analysis was performed to assess KLF5 protein expression in 425 primary EOC samples using tissue microarray. We also addressed the function of KLF5 in EOC and its interaction with signal transducer and activator of transcription 3 (STAT3) signaling pathway. We found that KLF5 overexpressed in 53% (229/425) of EOC samples, and is associated with aggressive markers. Forced expression of KLF5 enhanced cell growth in low expressing EOC cell line, MDAH2774. Conversely, knockdown of KLF5 reduced cell growth, migration, invasion and progression of epithelial to mesenchymal transition in KLF5 expressing cell lines, OVISE and OVSAHO. Importantly, silencing of KLF5 decreased the self-renewal ability of spheroids generated from OVISE and OVSAHO cell lines. In addition, downregulation of KLF5 potentiated the effect of cisplatin to induce apoptosis in these cell lines. These data reveals the pro-tumorigenic role of KLF5 in EOC and uncover its role in activation of STAT3 signaling pathway, suggesting the importance of KLF5 as a potential therapeutic target for EOC therapy.

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