Metformin inhibits melanoma cell metastasis by suppressing the miR-5100/SPINK5/STAT3 axis

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Abstract

Melanoma is the most lethal skin cancer characterized by its high metastatic potential. It is urgent to find novel therapy strategies to overcome this feature. Metformin has been confirmed to suppress invasion and migration of various types of cancer. However, additional mechanisms underlying the antimetastatic effect of metformin on melanoma require further investigation. Here, we performed microarray analysis and uncovered an altered mRNA and miRNA expression profile between melanoma and nevus. Luciferase reporter assay confirmed that miR-5100 targets SPINK5 to activate STAT3 phosphorylation. Migration and wound healing assays showed that the miR-5100/SPINK5/STAT3 axis promotes melanoma cell metastasis; the mechanism was proven by initiation of epithelial–mesenchymal transition. Co-immunoprecipitation (Co-IP) further confirmed an indirect interaction between SPINK5 and STAT3. Furthermore, metformin dramatically inhibited miR-5100/SPINK5/STAT3 pathway, and decreased B16-F10 cell metastasis to lung in C57 mouse module. Intriguingly, pretreatment of metformin before melanoma cell injection improved this effect further. These findings exposed the underlying mechanisms of action of metformin and update the use of this drug to prevent metastasis in melanoma.

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The online version contains supplementary material available at 10.1186/s11658-022-00353-5.

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Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.

Kenneth Livak, Thomas D. Schmittgen (2001)

The two most commonly used methods to analyze data from real-time, quantitative PCR experiments are absolute quantification and relative quantification. Absolute quantification determines the input copy number, usually by relating the PCR signal to a standard curve. Relative quantification relates the PCR signal of the target transcript in a treatment group to that of another sample such as an untreated control. The 2(-Delta Delta C(T)) method is a convenient way to analyze the relative changes in gene expression from real-time quantitative PCR experiments. The purpose of this report is to present the derivation, assumptions, and applications of the 2(-Delta Delta C(T)) method. In addition, we present the derivation and applications of two variations of the 2(-Delta Delta C(T)) method that may be useful in the analysis of real-time, quantitative PCR data. Copyright 2001 Elsevier Science (USA).

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Cancer Statistics, 2017.

Rebecca Siegel, Kimberly D Miller, Ahmedin Jemal (2017)

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data were collected by the National Center for Health Statistics. In 2017, 1,688,780 new cancer cases and 600,920 cancer deaths are projected to occur in the United States. For all sites combined, the cancer incidence rate is 20% higher in men than in women, while the cancer death rate is 40% higher. However, sex disparities vary by cancer type. For example, thyroid cancer incidence rates are 3-fold higher in women than in men (21 vs 7 per 100,000 population), despite equivalent death rates (0.5 per 100,000 population), largely reflecting sex differences in the "epidemic of diagnosis." Over the past decade of available data, the overall cancer incidence rate (2004-2013) was stable in women and declined by approximately 2% annually in men, while the cancer death rate (2005-2014) declined by about 1.5% annually in both men and women. From 1991 to 2014, the overall cancer death rate dropped 25%, translating to approximately 2,143,200 fewer cancer deaths than would have been expected if death rates had remained at their peak. Although the cancer death rate was 15% higher in blacks than in whites in 2014, increasing access to care as a result of the Patient Protection and Affordable Care Act may expedite the narrowing racial gap; from 2010 to 2015, the proportion of blacks who were uninsured halved, from 21% to 11%, as it did for Hispanics (31% to 16%). Gains in coverage for traditionally underserved Americans will facilitate the broader application of existing cancer control knowledge across every segment of the population. CA Cancer J Clin 2017;67:7-30. © 2017 American Cancer Society.

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Metformin and reduced risk of cancer in diabetic patients.

Josie M. M. Evans, Louise Donnelly, Alistair Emslie-Smith … (2005)

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Author and article information

Contributors

Xiao Yanbin: xiaoyanbin73@126.com

Wang Yunqing: kzwangyunqing@163.com

Li Zhen:

ORCID: http://orcid.org/0000-0001-5926-7832

lizhenres@163.com

Journal

Journal ID (nlm-ta): Cell Mol Biol Lett

Journal ID (iso-abbrev): Cell Mol Biol Lett

Title: Cellular & Molecular Biology Letters

Publisher: BioMed Central (London )

ISSN (Print): 1425-8153

ISSN (Electronic): 1689-1392

Publication date (Electronic): 15 June 2022

Publication date PMC-release: 15 June 2022

Publication date Collection: 2022

Volume: 27

Electronic Location Identifier: 48

Affiliations

[1 ]GRID grid.413389.4, ISNI 0000 0004 1758 1622, Department of Orthopaedics, , The Second Affiliated Hospital of Xuzhou Medical University, ; Xuzhou, 221000 People’s Republic of China

[2 ]GRID grid.452826.f, Department of Orthopaedics, , The Third Affiliated Hospital of Kunming Medical University, ; Kunming, 650118 People’s Republic of China

[3 ]GRID grid.413389.4, ISNI 0000 0004 1758 1622, Department of Medical Oncology, , The Second Affiliated Hospital of Xuzhou Medical University, ; Xuzhou, 221000 People’s Republic of China

[4 ]GRID grid.413389.4, ISNI 0000 0004 1758 1622, The Second Affiliated Hospital of Xuzhou Medical University, ; Xuzhou, 221000 People’s Republic of China

Author information

Li Zhen http://orcid.org/0000-0001-5926-7832

Article

Publisher ID: 353

DOI: 10.1186/s11658-022-00353-5

PMC ID: 9199130

PubMed ID: 35705923

SO-VID: 1f524bef-1a60-44d4-b1fe-7f63cd81a660

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/.

History

Date received : 10 February 2022

Date accepted : 31 May 2022

Funding

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

Award ID: 81760495

Award Recipient : Xiao Yanbin

Funded by: Basic Research Program of Xuzhou Health Commission

Award ID: KC21060

Award ID: KC21049

Award Recipient : Dong Suwei

Funded by: Development Foundation of Affiliated Hospital of Xuzhou Medical University

Award ID: XYFY2020001

Award ID: XYFY2020002

Award Recipient : Li Zhen

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Keywords: emt,mir-5100,metformin,spink5,stat3

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Keywords: emt, mir-5100, metformin, spink5, stat3

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Metformin inhibits melanoma cell metastasis by suppressing the miR-5100/SPINK5/STAT3 axis

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Microbiology Independent Research Journal (MIR Journal)

Most cited references 54

Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.

Cancer Statistics, 2017.

Metformin and reduced risk of cancer in diabetic patients.

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Cited by 8

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