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HOXB7 mediates cisplatin resistance in esophageal squamous cell carcinoma through involvement of DNA damage repair
- Source :
- Thoracic Cancer, Vol 11, Iss 11, Pp 3071-3085 (2020), Thoracic Cancer
- Publication Year :
- 2019
- Publisher :
- Wiley, 2019.
-
Abstract
- Background DNA damage repair is an important mechanism of platinum resistance. HOXB7 is one member of HOX family genes, which are essential developmental regulators and frequently dysregulated in cancer. Recently, its relevance in chemotherapy resistance and DNA damage repair has also been addressed. However, little is known regarding the association between HOXB7 and chemotherapy resistance in esophageal squamous cell carcinoma (ESCC). Methods The association between HOXB7 expression detected by immunohistochemisty and tumor regression grade (TRG) and long-term survival was analyzed in 143 ESCC patients who underwent neoadjuvant chemotherapy. CCK8 assay was used to examine the effect of cisplatin in a panel of four ESCC cell lines. A stable cell strain with HOXB7 knockdown of KYSE150 and KYSE450 was established to explore the effect on cisplatin sensitivity. The interaction of HOXB7 with Ku70, Ku80 and DNA-PKcs was determined by GST-pull down, coimmunoprecipitation and immunofluorescent colocalization. Finally, we investigated whether disrupting HOXB7 function by a synthetic peptide HXR9 blocking the formation of HOXB7/PBX could enhance cisplatin sensitivity in vitro and in vivo. Results High expression of HOXB7 was associated with cisplatin resistance and worse chemotherapy efficacy. HOXB7 knockdown reinforced cisplatin sensitivity. It was identified that HOXB7 interacts with Ku70, Ku80 and DNA-PKcs. HOXB7 knockdown was related to the downregulation of Ku70, Ku80 and DNA-PKcs as well as arrested cell cycle in S phase. HOXB7 inhibition by HXR9 had a synergistic effect to improve cisplatin sensitivity. Conclusion HOXB7 may be a biomarker for the prediction of chemoresistance of ESCC and serves as a promising therapeutic target.
- Subjects :
- Male
0301 basic medicine
Pulmonary and Respiratory Medicine
Ku80
medicine.medical_treatment
Mice, Nude
Transfection
lcsh:RC254-282
Mice
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
homeobox gene
Cell Line, Tumor
Biomarkers, Tumor
medicine
Animals
Humans
NHEJ
Homeodomain Proteins
Cisplatin
Gene knockdown
Chemotherapy
Ku70
business.industry
ESCC
Cancer
Original Articles
General Medicine
Cell cycle
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
medicine.disease
030104 developmental biology
Oncology
030220 oncology & carcinogenesis
Cancer research
Female
Original Article
Esophageal Squamous Cell Carcinoma
business
Chemoresistance
DNA Damage
medicine.drug
Subjects
Details
- ISSN :
- 17597714 and 17597706
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Thoracic Cancer
- Accession number :
- edsair.doi.dedup.....8d3840ee751813b38b0e15f2996fcc7a