cIAP-2 protein is upregulated by human papillomavirus in oropharyngeal cancers: role in radioresistance in vitro.

IF 3.1 2区医学 Q3 IMMUNOLOGY

Infectious Agents and Cancer Pub Date : 2024-09-27 DOI:10.1186/s13027-024-00609-z

Carolina Oliva, Diego Carrillo-Beltrán, Julio C Osorio, Iván Gallegos, Felipe Carvajal, Claudio Mancilla-Miranda, Paul Boettiger, Enrique Boccardo, Francisco Aguayo

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引用次数: 0

Abstract

Background: High-risk human papillomaviruses are the causal agents of a subset of head and neck cancers. A previous transcriptomic analysis showed that cIAP2 protein, involved in cell survival and apoptosis, is upregulated in OKF6 oral cells that express HPV16 E6/E7. In addition, cIAP2 promotes radioresistance, a very important concern in HNC treatment. However, cIAP2 increase has not yet been evaluated in oropharyngeal carcinomas (OPCs), nor has been the role of cIAP2 in HNC radioresistance.

Methods: We carried out a descriptive-analytical retrospective study in 49 OPCs from Chilean patients. We determined the expression of cIAP2 at transcript and proteins levels using reverse-transcriptase -polymerase chain reaction and immunohistochemistry, respectively. HPV and p16 expression were previously analyzed in these specimens. In addition, SCC-143 HNC cells ectopically expressing HPV16 E6/E7 were analyzed for cIAP2 expression and after transfection with a siRNA for HPV16 E6/E7 knocking down.

Results: We found a statistically significant association between HPV presence and cIAP2 expression (p = 0.0032 and p = 0.0061, respectively). An association between p16 and cIAP2 levels was also found (p = 0.038). When SCC-143 cells were transfected with a construct expressing HPV16 E6/E7, the levels of cIAP2 were significantly increased (p = 0.0383 and p = 0.0115, respectively). Conversely, HPV16 E6 and E7 knocking down resulted in a decrease of cIAP2 levels (p = 0.0161 and p = 0.006, respectively). Finally, cIAP2 knocking down in HPV16 E6/E7 cells resulted in increased apoptosis after exposure to radiation at 4 and 8 Gy (p = 0.0187 and p = 0.0061, respectively).

Conclusion: This study demonstrated for the first time a positive relationship between HPV presence and cIAP2 levels in OPCs. Additionally, cIAP2 knocking down sensitizes HNC cells to apoptosis promoted by radiation. Therefore, cIAP2 is a potential therapeutic target for radiation in HPV-driven HNC.

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人乳头瘤病毒在口咽癌中上调cIAP-2蛋白：在体外放射抗性中的作用。

背景：高危人类乳头状瘤病毒是导致部分头颈部癌症的病原体。之前的一项转录组分析显示，在表达 HPV16 E6/E7 的 OKF6 口腔细胞中，参与细胞存活和凋亡的 cIAP2 蛋白上调。此外，cIAP2 还会促进放射抗性，这也是 HNC 治疗中一个非常重要的问题。然而，尚未对口咽癌（OPCs）中 cIAP2 的增加进行评估，也未发现 cIAP2 在 HNC 抗放射中的作用：我们对智利患者的 49 例口咽癌进行了一项描述性分析回顾性研究。我们使用反转录聚合酶链反应和免疫组化技术分别测定了 cIAP2 在转录本和蛋白质水平上的表达。此前，我们已对这些标本中的 HPV 和 p16 表达进行了分析。此外，我们还分析了异位表达 HPV16 E6/E7 的 SCC-143 HNC 细胞的 cIAP2 表达情况，以及转染 siRNA 以敲除 HPV16 E6/E7 后的 cIAP2 表达情况：结果：我们发现 HPV 存在与 cIAP2 表达之间存在统计学意义上的显著关联（分别为 p = 0.0032 和 p = 0.0061）。我们还发现 p16 与 cIAP2 水平之间存在关联（p = 0.038）。当用表达 HPV16 E6/E7 的构建体转染 SCC-143 细胞时，cIAP2 的水平显著增加（分别为 p = 0.0383 和 p = 0.0115）。相反，敲除 HPV16 E6 和 E7 会导致 cIAP2 水平下降（分别为 p = 0.0161 和 p = 0.006）。最后，敲除 HPV16 E6/E7 细胞中的 cIAP2 会导致细胞在暴露于 4 Gy 和 8 Gy 辐射后凋亡增加（分别为 p = 0.0187 和 p = 0.0061）：本研究首次证明了OPCs中HPV的存在与cIAP2水平之间的正相关关系。此外，敲除 cIAP2 可使 HNC 细胞对辐射促进的细胞凋亡敏感。因此，cIAP2是辐射治疗HPV驱动的HNC的潜在治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Infectious Agents and Cancer ONCOLOGY-IMMUNOLOGY

CiteScore

5.80

自引率

2.70%

发文量

期刊介绍： Infectious Agents and Cancer is an open access, peer-reviewed online journal that encompasses all aspects of basic, clinical, epidemiological and translational research providing an insight into the association between chronic infections and cancer. The journal welcomes submissions in the pathogen-related cancer areas and other related topics, in particular: • HPV and anogenital cancers, as well as head and neck cancers; • EBV and Burkitt lymphoma; • HCV/HBV and hepatocellular carcinoma as well as lymphoproliferative diseases; • HHV8 and Kaposi sarcoma; • HTLV and leukemia; • Cancers in Low- and Middle-income countries. The link between infection and cancer has become well established over the past 50 years, and infection-associated cancer contribute up to 16% of cancers in developed countries and 33% in less developed countries. Preventive vaccines have been developed for only two cancer-causing viruses, highlighting both the opportunity to prevent infection-associated cancers by vaccination and the gaps that remain before vaccines can be developed for other cancer-causing agents. These gaps are due to incomplete understanding of the basic biology, natural history, epidemiology of many of the pathogens that cause cancer, the mechanisms they exploit to cause cancer, and how to interrupt progression to cancer in human populations. Early diagnosis or identification of lesions at high risk of progression represent the current most critical research area of the field supported by recent advances in genomics and proteomics technologies.