signature=3635e7ea23cafc7d364798f0ca0d188b,Endogenous APOBEC3B overexpression characterizes HPV-posi...

最新推荐文章于 2021-05-30 13:15:38 发布

转载最新推荐文章于 2021-05-30 13:15:38 发布 · 161 阅读

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研究发现，DNA胞嘧啶脱氨酶APOBEC3B（A3B）在多种人类肿瘤中，包括头颈癌，是一种新的内源性突变源。在高危人乳头瘤病毒（HPV）阳性的宫颈癌和头颈癌中，A3B过度表达显著，并与加速肿瘤发展和不良临床预后相关。HPV阳性肿瘤中A3B的过表达由病毒的E6/E7致癌蛋白引起。然而，在HPV阴性头颈癌中，A3B过表达的分子机制了解较少。本研究通过免疫组化方法揭示了在HPV阴性头颈癌中，A3B的表达从低到高逐渐增加，尤其是在高级别口腔上皮发育不良和口腔鳞状细胞癌中，A3B水平最高。A3B水平与Ki67得分的强烈正相关表明其可能与细胞周期有关。这些结果支持在HPV阴性肿瘤发展中A3B表达逐渐激活的模型，并提示A3B的过度表达可能成为高级别口腔发育不良和癌症的标志。

摘要：

The DNA cytosine deaminase APOBEC3B (A3B) is a newly recognized endogenous source of mutations in a range of human tumors, including head/neck cancer. A3B inflicts C-to-T and C-to-G base substitutions in 5′-TCA/T trinucleotide motifs, contributes to accelerated rates of tumor development, and affects clinical outcomes in a variety of cancer types. High-risk human papillomavirus (HPV) infection causes A3B overexpression, and HPV-positive cervical and head/neck cancers are among tumor types with the highest degree of APOBEC signature mutations. A3B overexpression in HPV-positive tumor types is caused by the viral E6/E7 oncoproteins and may be an early off-to-on switch in tumorigenesis. In comparison, less is known about the molecular mechanisms responsible for A3B overexpression in HPV-negative head/neck cancers. Here, we utilize an immunohistochemical approach to determine whether A3B is turned from off-to-on or if it undergoes a more gradual transition to overexpression in HPV-negative head/neck cancers. As positive controls, almost all HPV-positive oral epithelial dysplasias and oropharyngeal cancers showed high levels of nuclear A3B staining regardless of diagnosis. As negative controls, A3B levels were low in phenotypically normal epithelium adjacent to cancer and oral epithelial hyperplasias. Interestingly, HPV-negative and low-grade oral epithelial dysplasias showed intermediate A3B levels, while high-grade oral dysplasias showed high A3B levels similar to oral squamous cell carcinomas. A3B levels were highest in grade 2 and grade 3 oral squamous cell carcinomas. In addition, a strong positive association was found between nuclear A3B and Ki67 scores suggesting a linkage to the cell cycle. Overall, these results support a model in which gradual activation of A3B expression occurs during HPV-negative tumor development and suggest that A3B overexpression may provide a marker for advanced grade oral dysplasia and cancer.

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