J Cancer 2021; 12(4):1085-1093. doi:10.7150/jca.50746 This issue

Research Paper

Cigarette smoking promotes keratinocyte malignancy via generation of cancer stem-like cells

Shuchun Lin1,#, Wenfeng Mei1,#, Haichun Lai1,#, Xiufeng Li1,#, Huanjiao Weng1,#, Jiani Xiong1,2,5, Xiuyun Lin2, Tao Zeng1, Qiong Zhang1, Xing Liu1, Yunlu Xu1, Shubin Fang1, Rong Jin1, Xiaohua Hu1, Jieming Xie3, Jianbo Yang1,5, Yiqing Zheng4,5, Yuanzhong Chen1,✉, Jizhen Lin1,5,✉

1. The Cancer Center, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, Fujian 350001, China
2. Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, 420 Fuma Road, Fuzhou, Fujian 350011, China
3. The Department of Pharmacology, School of Pharmacy, Fujian Medical University, 1 Xue Yuan Road, University Town, Fuzhou, Fujian 350122, China
4. The Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Yat-sen Sun University,107 Yan Jiang West Road, Guangzhou, Guangdong 510120, China
5. The Immunotherapy Research Laboratory, Department of Otolaryngology, Cancer Center, University of Minnesota, 2001 6 th Street SE, Minneapolis 55455, MN, USA
#These authors contributed equally to this work

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Lin S, Mei W, Lai H, Li X, Weng H, Xiong J, Lin X, Zeng T, Zhang Q, Liu X, Xu Y, Fang S, Jin R, Hu X, Xie J, Yang J, Zheng Y, Chen Y, Lin J. Cigarette smoking promotes keratinocyte malignancy via generation of cancer stem-like cells. J Cancer 2021; 12(4):1085-1093. doi:10.7150/jca.50746. Available from https://www.jcancer.org/v12p1085.htm

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Objectives: Cigarette smoking is involved in the pathogenesis of head and neck squamous cell carcinoma (HNSCC). However, the underlying molecular mechanisms of cigarette smoking-induced HNSCC carcinogenesis are unclear and may involve cancer stem-like cell generation. We examined the effects of cigarette smoke condensate (CSC) on the formation of cancer stem-like cells, which are rich in octamer-binding transcription factor (OCT)-4, inhibitor of differentiation 1 (ID1), nuclear factor (NF)-κB, and B lymphoma Mo-MLV insertion region 1 homolog (BMI-1).

Materials and Methods: We used in vitro, in vivo, and archival human HNSCC tissue analysis to evaluate the effects of CSC on cancer stem-like cell formation.

Results: We found that CSC regulated OCT-4 expression, which subsequently regulated ID1 and NF-κB, at the promoter, mRNA, and protein levels in vitro. Furthermore, OCT-4 knockdown with siRNA reduced ID1 expression. ID1 and NF-κB synergistically increased the expression of BMI-1 and stimulated keratinocyte sphere generation. In vivo, ID1 and NF-κB acted together to generate malignant xenograft tumors, which were aggressive locally and systemically metastatic. Clinical data confirmed that ID1- and NF-κB-positive patients had poor clinical outcomes and 5-year disease-free survival.

Conclusion: Our data suggest that smoking cigarettes promoted cancer stem-like cell generation in the head and neck area via the OCT-4/ID1/NF-κB/BMI-1 signaling pathway.

Keywords: cigarette smoking, keratinocytes, cancer stem-like cells, octamer-binding transcription factor-4, B lymphoma Mo-MLV insertion region 1 homolog, head and neck squamous cell carcinoma