Hypoxia and HIF-1α Regulate Collagen Production in Keloids

Yuanyuan Kang; Mi Ryung Roh; Suvi Rajadurai; Anpuchchelvi Rajadurai; Raj Kumar; Ching Ni Njauw; Zhenlong Zheng; Hensin Tsao

doi:10.1016/j.jid.2020.01.036

Hypoxia and HIF-1α Regulate Collagen Production in Keloids

Yuanyuan Kang, Mi Ryung Roh, Suvi Rajadurai, Anpuchchelvi Rajadurai, Raj Kumar, Ching Ni Njauw, Zhenlong Zheng, Hensin Tsao

Department of Dermatology

Research output: Contribution to journal › Article › peer-review

19 Citations (Scopus)

Abstract

Keloids are reactive or spontaneous fibroproliferative dermal tumors characterized by the exaggerated and uncontrolled accumulation of extracellular collagen. Current approaches to mitigate keloidogenesis are largely procedural in nature. However, a better understanding of its biological drivers may lead to novel targeted treatments for keloids. Through whole-genome expression analysis, we found that an HIF-1α transcriptional footprint is preferentially upregulated (activation score = 2.024; P = 1.05E−19) in keloid fibroblasts compared with normal dermal fibroblasts. We verified that HIF-1α protein is more strongly expressed in keloid specimens compared with normal skin (P = 0.035) and that hypoxia (1% O₂) leads to increased collagen, especially in the extracellular compartment. Collagen levels were reduced uniformly by selective HIF-1α inhibitor CAY10585. Our results indicate that collagen secretion may be intimately linked to a hypoxic microenvironment within keloid tumors and that HIF-1α blockade could be a novel avenue of treatment for these tumors.

Original language	English
Pages (from-to)	2157-2165
Number of pages	9
Journal	Journal of Investigative Dermatology
Volume	140
Issue number	11
DOIs	https://doi.org/10.1016/j.jid.2020.01.036
Publication status	Published - 2020 Nov

Bibliographical note

Funding Information:
This study was supported in part by the Dept of Defense Air Force Office of Scientific Research (FA9550-10-1-0537 to HT), a faculty research grant of Yonsei University College of Medicine (6-2017-0078 to MRR), and institutional funds (to HT).

Funding Information:
This study was supported in part by the Dept of Defense Air Force Office of Scientific Research (FA9550-10-1-0537 to HT), a faculty research grant of Yonsei University College of Medicine (6-2017-0078 to MRR), and institutional funds (to HT). Conceptualization: YK, MRR, HT; Data Curation: YK, MRR, HT; Formal Analysis: YK, MRR, SR, HT; Funding Acquisition: MRR, HT; Investigation: YK, MRR, RK, AR, CN, ZZ; Methodology: YK, MRR, HT; Project Administration: HT; Supervision: HT; Validation: YK, MRR; Visualization: YK, MRR, HT; Writing - Original Draft Preparation: YK, MRR, AR, RK, HT; Writing - Review and Editing: YK, HT

Publisher Copyright:
© 2020 The Authors

All Science Journal Classification (ASJC) codes

Biochemistry
Molecular Biology
Dermatology
Cell Biology

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10.1016/j.jid.2020.01.036

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title = "Hypoxia and HIF-1α Regulate Collagen Production in Keloids",

abstract = "Keloids are reactive or spontaneous fibroproliferative dermal tumors characterized by the exaggerated and uncontrolled accumulation of extracellular collagen. Current approaches to mitigate keloidogenesis are largely procedural in nature. However, a better understanding of its biological drivers may lead to novel targeted treatments for keloids. Through whole-genome expression analysis, we found that an HIF-1α transcriptional footprint is preferentially upregulated (activation score = 2.024; P = 1.05E−19) in keloid fibroblasts compared with normal dermal fibroblasts. We verified that HIF-1α protein is more strongly expressed in keloid specimens compared with normal skin (P = 0.035) and that hypoxia (1% O2) leads to increased collagen, especially in the extracellular compartment. Collagen levels were reduced uniformly by selective HIF-1α inhibitor CAY10585. Our results indicate that collagen secretion may be intimately linked to a hypoxic microenvironment within keloid tumors and that HIF-1α blockade could be a novel avenue of treatment for these tumors.",

author = "Yuanyuan Kang and Roh, {Mi Ryung} and Suvi Rajadurai and Anpuchchelvi Rajadurai and Raj Kumar and Njauw, {Ching Ni} and Zhenlong Zheng and Hensin Tsao",

note = "Funding Information: This study was supported in part by the Dept of Defense Air Force Office of Scientific Research (FA9550-10-1-0537 to HT), a faculty research grant of Yonsei University College of Medicine (6-2017-0078 to MRR), and institutional funds (to HT). Funding Information: This study was supported in part by the Dept of Defense Air Force Office of Scientific Research (FA9550-10-1-0537 to HT), a faculty research grant of Yonsei University College of Medicine (6-2017-0078 to MRR), and institutional funds (to HT). Conceptualization: YK, MRR, HT; Data Curation: YK, MRR, HT; Formal Analysis: YK, MRR, SR, HT; Funding Acquisition: MRR, HT; Investigation: YK, MRR, RK, AR, CN, ZZ; Methodology: YK, MRR, HT; Project Administration: HT; Supervision: HT; Validation: YK, MRR; Visualization: YK, MRR, HT; Writing - Original Draft Preparation: YK, MRR, AR, RK, HT; Writing - Review and Editing: YK, HT Publisher Copyright: {\textcopyright} 2020 The Authors",

year = "2020",

month = nov,

doi = "10.1016/j.jid.2020.01.036",

language = "English",

volume = "140",

pages = "2157--2165",

journal = "Journal of Investigative Dermatology",

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AU - Kang, Yuanyuan

AU - Roh, Mi Ryung

AU - Rajadurai, Suvi

AU - Rajadurai, Anpuchchelvi

AU - Kumar, Raj

AU - Njauw, Ching Ni

AU - Zheng, Zhenlong

AU - Tsao, Hensin

N1 - Funding Information: This study was supported in part by the Dept of Defense Air Force Office of Scientific Research (FA9550-10-1-0537 to HT), a faculty research grant of Yonsei University College of Medicine (6-2017-0078 to MRR), and institutional funds (to HT). Funding Information: This study was supported in part by the Dept of Defense Air Force Office of Scientific Research (FA9550-10-1-0537 to HT), a faculty research grant of Yonsei University College of Medicine (6-2017-0078 to MRR), and institutional funds (to HT). Conceptualization: YK, MRR, HT; Data Curation: YK, MRR, HT; Formal Analysis: YK, MRR, SR, HT; Funding Acquisition: MRR, HT; Investigation: YK, MRR, RK, AR, CN, ZZ; Methodology: YK, MRR, HT; Project Administration: HT; Supervision: HT; Validation: YK, MRR; Visualization: YK, MRR, HT; Writing - Original Draft Preparation: YK, MRR, AR, RK, HT; Writing - Review and Editing: YK, HT Publisher Copyright: © 2020 The Authors

PY - 2020/11

Y1 - 2020/11

N2 - Keloids are reactive or spontaneous fibroproliferative dermal tumors characterized by the exaggerated and uncontrolled accumulation of extracellular collagen. Current approaches to mitigate keloidogenesis are largely procedural in nature. However, a better understanding of its biological drivers may lead to novel targeted treatments for keloids. Through whole-genome expression analysis, we found that an HIF-1α transcriptional footprint is preferentially upregulated (activation score = 2.024; P = 1.05E−19) in keloid fibroblasts compared with normal dermal fibroblasts. We verified that HIF-1α protein is more strongly expressed in keloid specimens compared with normal skin (P = 0.035) and that hypoxia (1% O2) leads to increased collagen, especially in the extracellular compartment. Collagen levels were reduced uniformly by selective HIF-1α inhibitor CAY10585. Our results indicate that collagen secretion may be intimately linked to a hypoxic microenvironment within keloid tumors and that HIF-1α blockade could be a novel avenue of treatment for these tumors.

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ER -

Hypoxia and HIF-1α Regulate Collagen Production in Keloids

Abstract

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