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