HERG1 promotes esophageal squamous cell carcinoma growth and metastasis through TXNDC5 by activating the PI3K/AKT pathway

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Abstract

Background

The human ether a-go-go-related gene 1 (HERG1) is involved in tumor progression; however, its role in esophageal squamous cell carcinoma (ESCC) is not well studied. This study investigated HERG1 function in ESCC progression and elucidated the underlying mechanisms.

Methods

The prognostic value of HERG1 was determined by immunohistochemistry in ESCC biopsies. Cell growth and proliferation were analyzed by colony formation and methyl thiazolyl tetrazolium assays. Cell migration and invasion were analyzed by wound healing and Boyden transwell assays. Epithelial-mesenchymal transition (EMT) was evaluated by immunoblotting and quantitative polymerase chain reaction (qPCR). A xenograft mouse model was used to validate the tumorigenic and metastatic roles of HERG1 in vivo.

Results

HERG1 expression was overall higher in ESCC tissues compared to adjacent non-tumor tissues. A retrospective analysis of 349 patients with ESCC (stages I–IV) confirmed increased HERG1 expression was associated with disease progression and higher mortality rate. The overall survival of the patients was significantly worse when their tumors displayed higher HERG1 expression. HERG1 knockdown reduced tumor growth and metastasis in athymic mice. HERG1 affected the proliferation, migration, and invasion of two ESCC cell lines (TE-1 and KYSE-30). Changes in HERG1 expression affected the expression of cell cycle- and EMT-related proteins; these effects were reversed by altering the expression of thioredoxin domain-containing protein 5 (TXNDC5), which is also associated with the clinicopathological characteristics of patients with ESCC and is relevant to HERG1 in pathological biopsies. Additionally, HERG1 expression altered phosphoinositide 3-kinase (PI3K) and AKT phosphorylation, thereby affecting TXNDC5 expression.

Conclusions

HERG1 contributes to poor prognosis in patients with ESCC by promoting ESCC cell proliferation, migration, and invasion via TXNDC5 through the PI3K/AKT signaling pathway. Our findings provided novel insights into the pathology of ESCC and role of HERG1 in tumor progression, suggesting that targeting HERG1 has potential diagnostic and therapeutic value for ESCC treatment.

Electronic supplementary material

The online version of this article (10.1186/s13046-019-1284-y) contains supplementary material, which is available to authorized users.

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Most cited references 35

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Spatial intratumor heterogeneity of genetic, epigenetic alterations and temporal clonal evolution in esophageal squamous cell carcinoma

Jia-Jie Hao, De-Chen Lin, Huy Dinh … (2016)

Esophageal squamous cell carcinoma (ESCC) is among the most common malignancies, but little is known about its spatial intratumor heterogeneity (ITH) and temporal clonal evolutionary processes. To address this, we performed multiregion whole-exome sequencing on 51 tumor regions from 13 ESCCs, and multiregion global methylation profiling on three of these 13 cases. We found an average of 35.8% heterogeneous somatic mutations with strong evidence of ITH. Half of driver mutations located on the branches targeted oncogenes, including PIK3CA, NFE2L2, MTOR, etc. By contrast, the majority of truncal and clonal driver mutations occurred in tumor suppressor genes, including TP53, KMT2D, ZNF750, etc. Interestingly, the phyloepigenetic trees robustly recapitulated the topologic structures of the phylogenetic ones, indicating the possible relationship between genetic and epigenetic alterations. Our integrated investigations of the spatial ITH and clonal evolution provide an important molecular foundation for enhanced understanding of the tumorigenesis and progression of ESCC.

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Elevated Orai1 and STIM1 expressions upregulate MACC1 expression to promote tumor cell proliferation, metabolism, migration, and invasion in human gastric cancer.

Na Huang, Min Shi, Jianping Bin … (2016)

ORAI calcium release-activated calcium modulator 1 (Orai1)- and stromal interacting molecule 1 (STIM1)-mediated store-operated Ca(2+) entry (SOCE) have been increasingly implicated in tumor progression; however, its role in gastric cancer (GC) is not well elucidated. We aimed to determine whether SOCE influences GC prognosis and elucidate the underlying mechanisms. Orai1 and STIM1 expressions were higher in GC tissues compared to adjacent non-tumor tissues according to RT-PCR and western blotting. Higher Orai1 and/or STIM1 expression was associated with more advanced disease, more frequent recurrence, and higher mortality rates in our study of 327 GC patients. The disease-free survival rates of Stage I-III patients and the overall survival rates of Stage IV patients were significantly worse when the tumors had high Orai1 and/or STIM1 expressions. Orai1 and/or STIM1 knockdown caused significantly reduced tumor growth and metastasis in athymic mice. Orai1 and/or STIM1 knockdown lowered the proliferation, metabolism, migration, and invasion of two GC cell lines. Also, Orai1 and/or STIM1 knockdown changed the markers of the cell cycle and epithelial-mesenchymal transition (EMT). These effects were reversed by metastasis-associated in colon cancer-1 (MACC1) overexpression. In summary, the composite molecules of SOCE suggest a poor prognosis for GC by promoting tumor cell proliferation, metabolism, migration, and invasion by targeting MACC1.

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Voltage-gated sodium channel Nav 1.7 promotes gastric cancer progression through MACC1-mediated upregulation of NHE1.

Jianling Xia, Na Huang, HONGXIANG HUANG … (2016)

Voltage-gated sodium channels (VGSCs), which are aberrantly expressed in several human cancers, affect cancer cell behavior; however, their role in gastric cancer (GC) and the link between these channels and tumorigenic signaling remain unclear. The aims of this study were to determine the clinicopathological significance and role of the VGSC Nav 1.7 in GC progression and to investigate the associated mechanisms. Here, we report that the SCN9A gene encoding Nav 1.7 was the most abundantly expressed VGSC subtype in GC tissue samples and two GC cell lines (BGC-823 and MKN-28 cells). SCN9A expression levels were also frequently found to be elevated in GC samples compared to nonmalignant tissues by real-time PCR. In the 319 GC specimens evaluated by immunohistochemistry, Nav 1.7 expression was correlated with prognosis, and transporter Na(+) /H(+) exchanger-1 (NHE1) and oncoprotein metastasis-associated in colon cancer-1 (MACC1) expression. Nav 1.7 suppression resulted in reduced voltage-gated sodium currents, decreased NHE1 expression, increased extracellular pH and decreased intracellular pH, and ultimately, reduced invasion and proliferation rates of GC cells and growth of GC xenografts in nude mice. Nav 1.7 inhibition led to reduced MACC1 expression, while MACC1 inhibition resulted in reduced NHE1 expression in vitro and in vivo. Mechanistically, the suppression of Nav 1.7 decreased NF-κB p65 nuclear translocation via p38 activation, thus reducing MACC1 expression. Downregulation of MACC1 decreased c-Jun phosphorylation and subsequently reduced NHE1 expression, whereas the addition of hepatocyte growth factor (HGF), a c-Met physiological ligand, reversed the effect. These results indicate that Nav 1.7 promotes GC progression through MACC1-mediated upregulation of NHE1. Therefore, Nav 1.7 is a potential prognostic marker and/or therapeutic target for GC.

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Author and article information

Contributors

Hongqiang Wang: 794086998@qq.com

Xuchun Yang: yangblood@163.com

Yan Guo: 17761228179@163.com

Lin Shui: skittyhi@foxmail.com

Shi Li: bubuxiong1989@qq.com

Yifeng Bai: 15756285949@163.com

Yu Liu: 14067599@qq.com

Ming Zeng: +86-28-87394152 , miller2002@yahoo.com

Jianling Xia: +86-28-87394133 , xiajianling@med.uestc.edu.cn

Journal

Journal ID (nlm-ta): J Exp Clin Cancer Res

Journal ID (iso-abbrev): J. Exp. Clin. Cancer Res

Title: Journal of Experimental & Clinical Cancer Research : CR

Publisher: BioMed Central (London )

ISSN (Print): 0392-9078

ISSN (Electronic): 1756-9966

Publication date (Electronic): 22 July 2019

Publication date PMC-release: 22 July 2019

Publication date Collection: 2019

Volume: 38

Electronic Location Identifier: 324

Affiliations

[1 ]ISNI 0000 0004 0369 4060, GRID grid.54549.39, Cancer Center, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, , Hospital of the University of Electronic Science and Technology of China, ; The Western First Round Road, Section 2#32, Chengdu, 610072 China

[2 ]ISNI 0000 0004 1799 3360, GRID grid.460175.1, Department of Oncology, , Zhejiang Province Zhoushan Hospital, ; Zhoushan, 316000 China

[3 ]Department of Oncology, West China Hospital, West China Medical Center, Sichuan University, Chengdu, 610041 China

[4 ]ISNI 0000 0004 1808 0918, GRID grid.414906.e, Department of Urology, , The First Affiliated Hospital of Wenzhou Medical University, ; Wenzhou, 325000 China

Article

Publisher ID: 1284

DOI: 10.1186/s13046-019-1284-y

PMC ID: 6647263

PubMed ID: 31331361

SO-VID: 611da672-b9f0-471e-b5ff-ce276c7361dd

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 18 January 2019

Date accepted : 19 June 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81702321

Award Recipient : Jianling Xia

Funded by: National Key Research and Development Program of China

Award ID: 2016YFC0105107

Award Recipient : Ming Zeng

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: esophageal squamous cell carcinoma,tumor progression,herg1,txndc5

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: esophageal squamous cell carcinoma, tumor progression, herg1, txndc5

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HERG1 promotes esophageal squamous cell carcinoma growth and metastasis through TXNDC5 by activating the PI3K/AKT pathway

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Abstract

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Methods

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Conclusions

Electronic supplementary material

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Cancer Immunotherapy

Most cited references 35

Spatial intratumor heterogeneity of genetic, epigenetic alterations and temporal clonal evolution in esophageal squamous cell carcinoma

Elevated Orai1 and STIM1 expressions upregulate MACC1 expression to promote tumor cell proliferation, metabolism, migration, and invasion in human gastric cancer.

Voltage-gated sodium channel Nav 1.7 promotes gastric cancer progression through MACC1-mediated upregulation of NHE1.

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Cited by 24

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