Acylglycerol kinase augments JAK2/STAT3 signaling in esophageal squamous cells

Chen, Xiuting; Ying, Zhe; Lin, Xi; Lin, Huan‐Xin; Wu, Jueheng; Li, Mengfeng; Song, Libing

doi:10.1172/jci68143

Cited by 62 publications

(88 citation statements)

References 60 publications

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“…STAT3 has been shown to regulate cancer cell stemness in several types of cancers, including breast cancer, glioblastoma, and ESCC (3,26). For instance, in ESCC, the JAK2/STAT3 pathway was shown to increase the side population cells and CD44 High cells (26), two subsets of ESCC cells that have been demonstrated to have cancer stem cell features (26,31).…”

Section: Discussionmentioning

confidence: 99%

“…Briefly, cells were gently dissociated with trypsin and stained with propidium iodide and Annexin V using the Annexin V-FITC Apoptosis Detection Kit I (BD Biosciences) according to the manufacturer's instructions. For side population cell identification, a previously described method was used (26). For CD44 detection, cells were gently dissociated with trypsin and stained with APC-conjugated CD44 antibody (BD pharmingen, 1:25) or the Mouse IgG2b, k isotype control antibody (BD pharmingen, 1:25), and flow cytometry analysis was performed.…”

Section: Chromatin Immunoprecipitation Coupled To Detection By Pcr (Cmentioning

confidence: 99%

“…2E). To directly quantify cancer stem cells, we performed Hoechst and CD44 staining, as reported in previous studies (26,31). As shown in Fig.…”

Section: Stat3b Decreases the Cancer Stem Cell Population And Sensitimentioning

confidence: 99%

“…Aberrant activation of STAT3 has been shown to promote tumorigenesis in this type of cancer (25)(26)(27)(28). Using ESCC as a study model, we examined the interaction between STAT3a and STAT3b in details, with the hope that the generated data can provide insights into the tumor suppressor role of STAT3b and the molecular mechanism underlying the dual role of STAT3 in cancers.…”

Section: Introductionmentioning

confidence: 99%

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The Opposing Function of STAT3 as an Oncoprotein and Tumor Suppressor Is Dictated by the Expression Status of STAT3β in Esophageal Squamous Cell Carcinoma

Zhang

Chen

et al. 2016

Clinical Cancer Research

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Purpose: STAT3 is known to have both oncogenic and tumor suppressive effects, but the regulation of these opposing effects is elusive. We hypothesized that STAT3b, one of the two STAT3 isoforms, is the key determinant in this context.Experimental Design: The prognostic significance of STAT3b and phospho-STAT3a Y705 (pSTAT3a Y705 ) was evaluated in 286 cases of patients with esophageal squamous cell carcinoma (ESCC). STAT3b-induced changes in the chemosensitivity to cisplatin and 5-fluorouracil were assessed both in vitro and in vivo. STAT3b-induced changes in the frequency of cancer stem cells were evaluated using Hoechst and CD44 staining. How STAT3b regulates STAT3a was determined using immunoprecipitation, confocal microscopy, DNA-binding, and chromatin immunoprecipitation-PCR.Results: STAT3b expression is an independent protective prognostic marker in patients with ESCC, which strongly correlated with longer overall survival (P ¼ 0.0009) and recurrence-free survival (P ¼ 0.0001). STAT3b significantly decreased the cancer stem cell population, and sensitized ESCC cells to cisplatin and 5-fluorouracil in tumor xenografts. Mechanistically, STAT3b markedly attenuated the transcription activity of STAT3a via inducing STAT3a:STAT3b heterodimers. However, the heterodimer formation decreased the binding between STAT3a and PTPN9 (better known as PTP-MEG2), a protein tyrosine phosphatase, thereby promoting the phosphorylation of STAT3a Y705 and enhancing its nuclear translocation and DNA binding. Correlating with this, high STAT3b expression converts the prognostic value of pSTAT3a Y705 from unfavorable to favorable in patients with ESCC.Conclusions: STAT3b suppresses chemoresistance and cancer stemness by blocking the transcriptional activity of STAT3a. The paradoxical increase in pSTAT3a Y705 induced by STAT3b carries important implications as to how the biologic and prognostic significance of STAT3 in cancers should be interpreted. Clin Cancer Res; 22(3); 691-703. Ó2015 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Chromatin Immunoprecipitation Coupled To Detection By Pcr (Cmentioning

confidence: 99%

“…2E). To directly quantify cancer stem cells, we performed Hoechst and CD44 staining, as reported in previous studies (26,31). As shown in Fig.…”

Section: Stat3b Decreases the Cancer Stem Cell Population And Sensitimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Opposing Function of STAT3 as an Oncoprotein and Tumor Suppressor Is Dictated by the Expression Status of STAT3β in Esophageal Squamous Cell Carcinoma

Zhang

Chen

et al. 2016

Clinical Cancer Research

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“…Overexpression of AGK has previously been shown to constitutively activate janus kinase 2/signal transducer and activator of transcription 3, consequently augmenting the tumorigenicity of esophageal squamous cell carcinoma cells (12). In addition, the expression of AGK has been shown to be associated with the development and progression of prostate cancer (13).…”

Section: Discussionmentioning

confidence: 99%

Acylglycerol kinase promotes the proliferation and cell cycle progression of oral squamous cell carcinoma

Liu

Ren

Gao

et al. 2015

Molecular Medicine Reports

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Abstract. Cell proliferation is a major underlying cause of mortality amongst patients with oral squamous cell carcinoma (OSCC); however, the underlying mechanisms have remained to be elucidated. Acylglycerol kinase (AGK) is a multisubstrate lipid kinase, which is known to be associated with the progression of various types of human cancer. The present study aimed to investigate the role of AGK in cell proliferation and cell cycle progression in OSCC. The expression levels of AGK were detected in cancerous and adjacent normal tissue samples from four patients with OSCC undergoing surgical resection, and in OSCC cell lines, using the polymerase chain reaction (PCR) and western blot analysis. The effects of AGK on the proliferation and cell cycle progression of OSCC cells were assessed using a short hairpin RNA lentivirus or expressed-plasmid transfection. In addition, the expression levels of cyclin D1 and p21, as well as cell proliferation-and cell cycle-associated proteins were detected by PCR and western blotting. The results of the present study demonstrated that the expression levels of AGK were significantly higher in the cancerous tissues and OSCC cell lines, compared with the adjacent normal tissues and control cells, respectively. Furthermore, MTT and colony formation assays, in addition to flow cytometric analysis were conducted, in order to assess the role of AGK in cell proliferation and cell cycle progression. The cell proliferation and cell cycle progression of an established OSCC cell line were demonstrated to be decreased following AGK knockdown, and enhanced by AGK overexpression in vitro. Aberrant AGK expression in OSCC was shown to be associated with cell proliferation and cell cycle progression. The results of the present study provide evidence that AGK may promote cell proliferation and cell cycle progression in OSCC.

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Mitochondrial protein import dysfunction: mitochondrial disease, neurodegenerative disease and cancer

2021

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The majority of proteins localised to mitochondria are encoded by the nuclear genome, with approximately 1500 proteins imported into mammalian mitochondria. Dysfunction in this fundamental cellular process is linked to a variety of pathologies including neuropathies, cardiovascular disorders, myopathies, neurodegenerative diseases and cancer, demonstrating the importance of mitochondrial protein import machinery for cellular function. Correct import of proteins into mitochondria requires the co‐ordinated activity of multimeric protein translocation and sorting machineries located in both the outer and inner mitochondrial membranes, directing the imported proteins to the destined mitochondrial compartment. This dynamic process maintains cellular homeostasis, and its dysregulation significantly affects cellular signalling pathways and metabolism. This review summarises current knowledge of the mammalian mitochondrial import machinery and the pathological consequences of mutation of its components. In addition, we will discuss the role of mitochondrial import in cancer, and our current understanding of the role of mitochondrial import in neurodegenerative diseases including Alzheimer's disease, Huntington's disease and Parkinson's disease.

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Acylglycerol kinase augments JAK2/STAT3 signaling in esophageal squamous cells

Abstract: JAK2 activity is tightly controlled through a self-inhibitory effect via its JAK homology domain 2 (JH2),

Cited by 62 publications

References 60 publications

The Opposing Function of STAT3 as an Oncoprotein and Tumor Suppressor Is Dictated by the Expression Status of STAT3β in Esophageal Squamous Cell Carcinoma

The Opposing Function of STAT3 as an Oncoprotein and Tumor Suppressor Is Dictated by the Expression Status of STAT3β in Esophageal Squamous Cell Carcinoma

Acylglycerol kinase promotes the proliferation and cell cycle progression of oral squamous cell carcinoma

Mitochondrial protein import dysfunction: mitochondrial disease, neurodegenerative disease and cancer

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