Down-regulation of kappa opioid receptor promotes ESCC proliferation, invasion and metastasis via the PDK1-AKT signaling pathway

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Abstract

Background

As a class of the opioid receptors, the kappa opioid receptor (KOR) has been verified to be a potential biomarker and therapeutic target for human malignant tumors. However, a thorough understanding of whether KOR affects progression of esophageal squamous cell carcinoma (ESCC) is still lacking. This study focused on exploring the effect of knocking down KOR in ESCC and its underlying mechanism.

Methods

Bioinformatics analysis was used to compare the different expression level of OPRK1 (KOR gene) in tumor and adjacent normal tissues, and predict the relationship between KOR expression and overall survival. RNA-sequence analysis was performed to detect the altered functions and mechanisms after down regulating KOR. The in vitro and in vivo assays were used to detect the effects of down-regulated KOR on cell proliferation, migration and invasion. Substrate gel zymography and 3D cell culture assays were used to find the effect of KOR knockdown on the degradation of extracellular matrix (ECM), and immunefluorescence was performed to detect the altered cytoskeleton. Western blotting and immunohistochemistry were used to explore the underlying mechanism pathway.

Results

Bioinformatics analysis revealed that the expression of OPRK1 was lower in tumor tissue than that in adjacent normal tissues, and lowered expression of KOR was associated with poorer overall survival. The in vitro assays demonstrated that down-regulation of KOR enhanced ESCC proliferation, metastasis and invasion. Western blotting revealed that down-regulation of KOR could activate PDK1-AKT signaling pathway, which actively regulated the cancer progression. Down-regulation of KOR enhanced the formation of invadopodia, secretion of matrix metalloproteinase-2 (MMP2) and rearrangement of cytoskeleton, which were positively related with the invasion of ESCC. KOR knockdown enhanced the tumor invasion and elevated the AKT phosphorylation in nude mice. The AKT kinase inhibition could reverse the effect of down-regulation of KOR.

Conclusion

KOR might act as a tumor suppressor in ESCC and down-regulation of KOR could enhance the ESCC tumor phenotype.

Graphical abstract

Supplementary Information

The online version contains supplementary material available at 10.1186/s12964-022-00833-3.

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Most cited references 33

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Global Cancer Incidence and Mortality Rates and Trends--An Update

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There are limited published data on recent cancer incidence and mortality trends worldwide. We used the International Agency for Research on Cancer's CANCERMondial clearinghouse to present age-standardized cancer incidence and death rates for 2003-2007. We also present trends in incidence through 2007 and mortality through 2012 for select countries from five continents. High-income countries (HIC) continue to have the highest incidence rates for all sites, as well as for lung, colorectal, breast, and prostate cancer, although some low- and middle-income countries (LMIC) now count among those with the highest rates. Mortality rates from these cancers are declining in many HICs while they are increasing in LMICs. LMICs have the highest rates of stomach, liver, esophageal, and cervical cancer. Although rates remain high in HICs, they are plateauing or decreasing for the most common cancers due to decreases in known risk factors, screening and early detection, and improved treatment (mortality only). In contrast, rates in several LMICs are increasing for these cancers due to increases in smoking, excess body weight, and physical inactivity. LMICs also have a disproportionate burden of infection-related cancers. Applied cancer control measures are needed to reduce rates in HICs and arrest the growing burden in LMICs.

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Fang-Liang Huang, Sheng-Jie Yu (2018)

The poor prognosis and rising incidence of esophageal cancer highlight the need for improved detection and prediction methods that are essential prior to treatment. Esophageal cancer is one of the most fatal malignancies worldwide, with a dramatic increase in incidence in the Western world occurring over the past few decades. Despite improvements in the management and treatment of esophageal cancer patients, the general outcome remains very poor for overall 5-year survival rates (∼10%) and 5-year postesophagectomy survival rates (∼15-40%). Esophageal cancer is often diagnosed during its advanced stages, the main reason being the lack of early clinical symptoms. In an attempt to improve the outcome of patients after surgery, such patients are often treated with neoadjuvent concurrent chemoradiotherapy (CCRT) in order to decrease tumor size. However, CCRT may enhance toxicity levels and possibly cause a delay in surgery for patients who respond poorly to CCRT. Thus, precise biomarkers that could predict or identify patients who may or may not respond well to CCRT can assist physicians in choosing the appropriate therapy for patients. Identifying susceptible gene and biomarkers can help in predicting the treatment response of patients while improving their survival rates.

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Akt in cancer: mediator and more

Sundaramoorthy Revathidevi, Arasambattu Kannan Munirajan (2019)

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Author and article information

Contributors

Ze-Peng Du: zepdu@126.com

Yong-Fa Zhang:

ORCID: http://orcid.org/0000-0001-5036-2702

10yfzhang1@stu.edu.cn

Journal

Journal ID (nlm-ta): Cell Commun Signal

Journal ID (iso-abbrev): Cell Commun Signal

Title: Cell Communication and Signaling : CCS

Publisher: BioMed Central (London )

ISSN (Electronic): 1478-811X

Publication date (Electronic): 19 March 2022

Publication date PMC-release: 19 March 2022

Publication date Collection: 2022

Volume: 20

Electronic Location Identifier: 35

Affiliations

[1 ]GRID grid.452836.e, ISNI 0000 0004 1798 1271, Department of Anesthesiology, , Second Affiliated Hospital of Shantou University Medical College, ; Shantou, 515041 People’s Republic of China

[2 ]GRID grid.452734.3, Central Laboratory, , Shantou Central Hospital, ; Shantou, 515041 People’s Republic of China

[3 ]GRID grid.452734.3, Department of Pathology, , Shantou Central Hospital, ; Shantou, 515041 People’s Republic of China

[4 ]GRID grid.411679.c, ISNI 0000 0004 0605 3373, Department of Physiology, , Shantou University Medical College, ; Shantou, 515041 People’s Republic of China

[5 ]Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen, 518067 People’s Republic of China

Author information

Yong-Fa Zhang http://orcid.org/0000-0001-5036-2702

Article

Publisher ID: 833

DOI: 10.1186/s12964-022-00833-3

PMC ID: 8934502

PubMed ID: 35305679

SO-VID: 818c7574-365d-41bb-8c66-a2faae6db722

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data.

History

Date received : 23 July 2021

Date accepted : 29 January 2022

Funding

Funded by: medical research foundation of guangdong province

Award ID: No.A2015026

Award Recipient : Yong-Fa Zhang

Funded by: the natural science foundation of guangdong province

Award ID: No.2018A030313069

Award Recipient : Yong-Fa Zhang

Funded by: FundRef http://dx.doi.org/10.13039/501100003453, Natural Science Foundation of Guangdong Province;

Award ID: No.2016A030313069

Award Recipient : Xin-Hua He

Funded by: the doctoral foundation of shantou university medical college

Award ID: No.413796

Award Recipient : Xin-Hua He

Custom metadata

ScienceOpen disciplines: Cell biology

Keywords: kappa opioid receptor,pdk1,akt,escc

Data availability:

ScienceOpen disciplines: Cell biology

Keywords: kappa opioid receptor, pdk1, akt, escc

Down-regulation of kappa opioid receptor promotes ESCC proliferation, invasion and metastasis via the PDK1-AKT signaling pathway

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Abstract

Background

Methods

Results

Conclusion

Graphical abstract

Supplementary Information

Related collections

Claudins

Most cited references 33

Global Cancer Incidence and Mortality Rates and Trends--An Update

Esophageal cancer: Risk factors, genetic association, and treatment.

Akt in cancer: mediator and more

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Contributors

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Affiliations

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History

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