Human papillomavirus associated XPF deficiency increases alternative end joining and cisplatin sensitivity in head and neck squamous cell carcinoma

Zuo, Nan1,2; Ma, Lin3; Liu, Tianyang1,2; Hu, Weitao3; Luo, Yupeng4; Meng, He3; Ren, Qiushi2,5; Deng, Yongqiang3; Wei, Lanlan1,6,7; Liu, Qi2,8

2023-05-01

10.1016/j.oraloncology.2023.106367

ORAL ONCOLOGY   影响因子和分区

1368-8375

1879-0593

Objectives: Human papillomavirus (HPV) positive head and neck squamous cell carcinoma (HNSCC) showed a considerably better prognosis with greater cisplatin sensitivity compared to their HPV-negative counterparts. Deciphering the underlying molecular mechanisms for HPV-induced cisplatin sensitivity is imperative to improve the prognosis of HPV-negative HNSCC. Materials and Methods: The Fanconi anemia (FA) pathway status in HNSCC cells was analysed by detecting the cell cycle and chromosomal aberrations. XPF expression was validated using PCR, western blot, and immunohistochemistry. Droplet digital PCR and GFP expressing reporter assay were used to analyse the changes in alternative end-joining (alt-EJ) levels. The cisplatin sensitization was verified by cell proliferation assay, clonogenic cell survival assay, and TUNEL. Results: HPV-positive HNSCC cells showed significant prolonged G2-M cell cycle arrest and aberrant chromosome formation under interstrand crosslinker treatment. Both mRNA and protein expression of XPF were considerably decreased in HPV-positive HNSCC, according to the analysis of cellular and clinical data. XPF inhibition upregulated the activity of the alt-EJ pathway in HPV-negative HNSCC cells by 32.02% (P < 0.001) but had little effect on HPV-positive HNSCC. Consistent with this, simultaneous suppression of XPF and alt-EJ enhanced cisplatin sensitivity of HPV-negative HNSCC in vitro and in vivo. Conclusion: HPV-positive HNSCC cells exhibit a profound FA pathway deficiency associated with reduced XPF expression. HNSCC cells with compromised XPF function are more reliant on the alt-EJ pathway for genomic stability. Combining FA and alt-EJ inhibition may be used to cope with the hard-to-treat HPV-negative HNSCC.

Alternative end-joining Cisplatin DNA damage repair Fanconi anemia HNSCC HPV XPF

SCI

英语

通讯

National Science Foundation of China["82073007","82203967"] ; Shenzhen Science and Technology RD Fund[JCYJ20210324131607019] ; third foster plan in 2019 "Molecular Imaging Probe Preparation and Characterization of Key Technologies and Equipment" for the development of key technologies and equipment in major science and technology infrastructure in Shenzhen[ZDKJ20190305003] ; Science Technology and Innovation Committee of Shenzhen Municipality[20200812112320001] ; Shenzhen University[2023A1515011945] ; null[S202210590051]

Oncology ; Dentistry, Oral Surgery & Medicine

Oncology ; Dentistry, Oral Surgery & Medicine

WOS:000967569500001

ELSEVIER

CLINICAL MEDICINE

Web of Science

1.Harbin Med Univ, Hosp 1, Dept Stomatol, Harbin, Peoples R China
2.Shenzhen Bay Lab, Shenzhen, Peoples R China
3.Shenzhen Univ, Shenzhen Univ Gen Hosp, Dept Stomatol, Shenzhen, Peoples R China
4.Shenzhen Univ, Sch Stomatol, Shenzhen, Peoples R China
5.Peking Univ, Shenzhen Grad Sch, Inst Biomed Engn, Shenzhen, Peoples R China
6.Third Peoples Hosp Shenzhen, Inst Hepatol, Natl Clin Res Ctr Infect Dis, Shenzhen, Peoples R China
7.Southern Univ Sci & Technol, Hosp 2, Shenzhen, Peoples R China
8.Shenzhen Univ Sch Med, Int Canc Ctr, Shenzhen, Peoples R China

Zuo, Nan,Ma, Lin,Liu, Tianyang,et al. Human papillomavirus associated XPF deficiency increases alternative end joining and cisplatin sensitivity in head and neck squamous cell carcinoma[J]. ORAL ONCOLOGY,2023,140.

Zuo, Nan.,Ma, Lin.,Liu, Tianyang.,Hu, Weitao.,Luo, Yupeng.,...&Liu, Qi.(2023).Human papillomavirus associated XPF deficiency increases alternative end joining and cisplatin sensitivity in head and neck squamous cell carcinoma.ORAL ONCOLOGY,140.

Zuo, Nan,et al."Human papillomavirus associated XPF deficiency increases alternative end joining and cisplatin sensitivity in head and neck squamous cell carcinoma".ORAL ONCOLOGY 140(2023).