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

Shuchun Lin, Wenfeng Mei, Haichun Lai, Xiufeng Li, Huanjiao Weng, Jiani Xiong, Xiuyun Lin, Tao Zeng, Qiong Zhang, Xing Liu, Yunlu Xu, Shubin Fang, Rong Jin, Xiaohua Hu, Jieming Xie, Jianbo Yang, Yiqing Zheng, Yuanzhong Chen, Jizhen Lin

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1085-1093
Number of pages9
JournalJournal of Cancer
Volume12
Issue number4
DOIs
StatePublished - Jan 1 2021

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health grants [grant number R03CA107989]; the Brainstorm Award from the University of Minnesota Cancer Center, 5M Lions International Hearing Foundation and Natural Science Foundation of Fujian Province [grant number 2016J01460] for study design, the collection, analysis and interpretation of data; the Industry-University-Research Cooperation Project of Fujian [grant number 2017Y4006]; and Startup Fund for Scientific Research, Fujian Medical University [grant number 2017XQ1021] for analysis and interpretation of data and the decision to submit the article for publication.

Keywords

  • B lymphoma Mo-MLV insertion region 1 homolog
  • Cancer stem-like cells
  • Cigarette smoking
  • Head
  • Keratinocytes
  • Neck squamous cell carcinoma
  • Octamer-binding transcription factor-4

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