Emerging Insights into Keratin 16 Expression during Metastatic Progression of Breast Cancer

Elazezy, Maha; Schwentesius, Sandra; Stegat, Luisa; Wikman, Harriet; Werner, Stefan; Mansour, Wael Y.; Failla, Antonio Virgilio; Peine, Sven; Müller, Volkmar; Thiery, Jean Paul; Ebrahimi Warkiani, Majid; Pantel, Klaus; Joosse, Simon A.

doi:10.3390/cancers13153869

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Emerging Insights into Keratin 16 Expression during Metastatic Progression of Breast Cancer

¹,

¹,

¹,

¹,

Antonio Virgilio Failla

³,

Sven Peine

⁴,

Volkmar Müller

⁵

Jean Paul Thiery

⁶,

Majid Ebrahimi Warkiani

⁷,

Klaus Pantel

and

Simon A. Joosse

^1,*

Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany

Department of Radiotherapy and Radiation Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany

UKE Microscopy Imaging Facility (UMIF), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany

⁴

Department of Transfusion Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany

⁵

Department of Gynecology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany

⁶

Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510320, China

⁷

School of Biomedical Engineering, University of Technology Sydney, Sydney 2007, Australia

Author to whom correspondence should be addressed.

Academic Editor: Marija Balić

Cancers 2021, 13(15), 3869; https://doi.org/10.3390/cancers13153869

Received: 8 July 2021 / Revised: 25 July 2021 / Accepted: 26 July 2021 / Published: 31 July 2021

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The mechanisms leading to tumor metastasis remain poorly understood, and therefore, phenotyping of circulating tumor cells from cancer patients may contribute to translating these mechanisms. In in silico analysis, high expression of keratin 16 was associated with higher tumor aggressiveness. According to our results, keratin 16 is a metastasis-associated protein that promotes EMT and acts as a positive regulator of cellular motility by reorganizing the actin cytoskeleton, which is the driving force behind disrupting intercellular adhesion and directional migration. In metastatic breast cancer patients, circulating tumor cells expressing keratin 16 were associated with shorter relapse-free survival. This is an important issue for future research to determine the exact function of keratin 16 in tumor dissemination and metastasis development by analyzing keratin 16 status in disseminating tumor cells. Furthermore, gaining a better knowledge of keratin 16’s biology would give crucial mechanistic insights that might lead to a unique treatment option.

Abstract

Keratins are the main identification markers of circulating tumor cells (CTCs); however, whether their deregulation is associated with the metastatic process is largely unknown. Previously we have shown by in silico analysis that keratin 16 (KRT16) mRNA upregulation might be associated with more aggressive cancer. Therefore, in this study, we investigated the biological role and the clinical relevance of K16 in metastatic breast cancer. By performing RT-qPCR, western blot, and immunocytochemistry, we investigated the expression patterns of K16 in metastatic breast cancer cell lines and evaluated the clinical relevance of K16 expression in CTCs of 20 metastatic breast cancer patients. High K16 protein expression was associated with an intermediate mesenchymal phenotype. Functional studies showed that K16 has a regulatory effect on EMT and overexpression of K16 significantly enhanced cell motility (p < 0.001). In metastatic breast cancer patients, 64.7% of the detected CTCs expressed K16, which was associated with shorter relapse-free survival (p = 0.0042). Our findings imply that K16 is a metastasis-associated protein that promotes EMT and acts as a positive regulator of cellular motility. Furthermore, determining K16 status in CTCs provides prognostic information that helps to identify patients whose tumors are more prone to metastasize. View Full-Text

Keywords: circulating tumor cells (CTCs); keratin 16 (KRT16); epithelial to mesenchymal transition (EMT)

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Elazezy, M.; Schwentesius, S.; Stegat, L.; Wikman, H.; Werner, S.; Mansour, W.Y.; Failla, A.V.; Peine, S.; Müller, V.; Thiery, J.P.; Ebrahimi Warkiani, M.; Pantel, K.; Joosse, S.A. Emerging Insights into Keratin 16 Expression during Metastatic Progression of Breast Cancer. Cancers 2021, 13, 3869. https://doi.org/10.3390/cancers13153869

AMA Style

Elazezy M, Schwentesius S, Stegat L, Wikman H, Werner S, Mansour WY, Failla AV, Peine S, Müller V, Thiery JP, Ebrahimi Warkiani M, Pantel K, Joosse SA. Emerging Insights into Keratin 16 Expression during Metastatic Progression of Breast Cancer. Cancers. 2021; 13(15):3869. https://doi.org/10.3390/cancers13153869

Chicago/Turabian Style

Elazezy, Maha, Sandra Schwentesius, Luisa Stegat, Harriet Wikman, Stefan Werner, Wael Y. Mansour, Antonio Virgilio Failla, Sven Peine, Volkmar Müller, Jean Paul Thiery, Majid Ebrahimi Warkiani, Klaus Pantel, and Simon A. Joosse. 2021. "Emerging Insights into Keratin 16 Expression during Metastatic Progression of Breast Cancer" Cancers 13, no. 15: 3869. https://doi.org/10.3390/cancers13153869

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Emerging Insights into Keratin 16 Expression during Metastatic Progression of Breast Cancer

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