Infection with high-risk human papillomavirus (HR-HPV) is the main cause of cervical cancer (CC), but viral infection alone does not guarantee the development of this malignancy. Indeed, deficiencies of dietary micronutrients could favor cervical cancer development in individuals that harbor HR-HPV infections. The status of retinoid levels, natural and synthetic derivatives of vitamin A, is important in maintaining cellular differentiation of the cervical epithelium. Moreover, many studies show a link between deficient intake of retinoids or alteration of the retinoid receptors and CC development. In spite of this, the effect of vitamin A deficiency (VAD) in presence of HR-HPV oncoproteins on cervical carcinogenesis in vivo has not been reported. Transgenic mice expressing E6 or E7 oncoproteins (K14E6 or K14E7 mice, respectively) were used to evaluate the possible role of VAD in the development of malignant cervical lesions. The survival of the mice in VAD condition was studied, and histopathological analysis and immunohistochemical detection of molecular cancer markers such as the tumor suppressor retinoic acid receptor beta (RARβ), proliferating cell nuclear antigen (PCNA), cleaved caspase 3, and the tumor suppressor protein p16^INK4A (inhibitor of CDK4) were performed. Our results show that K14E6/VAD mice showed moderate cervical dysplasia; notably, K14E7/VAD mice developed severe cervical dysplasia and cervical in situ carcinoma at an early age. VAD synergizes with HPV16E7 oncoprotein expression favoring cervical carcinogenesis in vivo.

中文翻译：

---

表达K14E7HPV的转基因小鼠维生素A缺乏促进恶性宫颈病变的形成

感染高危型人乳头瘤病毒 (HR-HPV) 是宫颈癌 (CC) 的主要原因，但仅靠病毒感染并不能保证这种恶性肿瘤的发展。事实上，饮食微量营养素的缺乏可能有利于感染 HR-HPV 的个体发生宫颈癌。维生素 A 的天然和合成衍生物类维生素 A 水平的状态对于维持宫颈上皮细胞分化很重要。此外，许多研究表明类维生素 A 摄入不足或类维生素 A 受体改变与 CC 发展之间存在联系。尽管如此，尚未报道维生素 A 缺乏 (VAD) 在 HR-HPV 癌蛋白存在下对体内宫颈癌发生的影响。表达 E6 或 E7 癌蛋白的转基因小鼠（K14E6 或 K14E7 小鼠，分别）用于评估 VAD 在恶性宫颈病变发展中的可能作用。研究了VAD条件下小鼠的存活情况，并对肿瘤抑制因子视黄酸受体β（RARβ）、增殖细胞核抗原（PCNA）、cleaved caspase 3和肿瘤抑制因子等癌症分子标志物进行了组织病理学分析和免疫组化检测。 p16蛋白^{进行了 INK4A}（CDK4 抑制剂）。我们的结果表明 K14E6/VAD 小鼠表现出中度宫颈发育不良；值得注意的是，K14E7/VAD 小鼠在很小的时候就出现了严重的宫颈发育不良和宫颈原位癌。VAD 与 HPV16E7 癌蛋白表达协同促进体内宫颈癌发生。