Unlocking the Role of a Genital Herpesvirus, Otarine Herpesvirus 1, in California Sea Lion Cervical Cancer.
Unlocking the Role of a Genital Herpesvirus, Otarine Herpesvirus 1, in California Sea Lion Cervical Cancer.
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DOI：
10.3390/ani11020491
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发表时间：
2021-02-13
期刊：
影响因子：
--
通讯作者：
Gulland FMD
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文献类型：
--
作者：
Deming AC;Wellehan JFX;Colegrove KM;Hall A;Luff J;Lowenstine L;Duignan P;Cortés-Hinojosa G;Gulland FMD
野生加州海狮（Zalophus californianus）泌尿生殖系统癌的发病率很高。癌症开始于海狮的生殖道，然后扩散到其他器官，导致死亡。先前的研究已经在大多数患有泌尿生殖器癌的海狮的生殖道中鉴定出疱疹病毒，耳疱疹病毒1（OtHV 1），然而，这种病毒也在没有癌症的海狮的生殖道中发现，使得其在泌尿生殖器癌中的作用模糊不清。在这里，95只患有癌症的海狮和163只没有癌症的海狮的组织进行了OtHV 1检测，定量了病毒的数量，并测量了病毒基因的表达。OtHV 1被发现在100%的海狮与泌尿生殖器癌和有异常高的病毒载量和病毒基因表达的生殖器肿瘤。在没有患癌症的海狮中，36%的海狮疱疹病毒检测呈阳性，它们的病毒载量要低得多，没有可检测到的病毒基因表达，这表明疱疹病毒处于休眠状态。这些发现支持生殖器疱疹病毒在海狮泌尿生殖器癌中起着不可或缺的作用，并表明存在潜在的触发因素或事件，导致病毒在一些受感染的海狮中诱发癌症，而不是其他海狮。加州海狮的泌尿生殖道癌是海洋哺乳动物最常见的癌症。原发性肿瘤发生在子宫颈、阴道、阴茎或包皮，并且侵袭性转移导致死亡。这种癌症与性传播疱疹病毒，otarine疱疹病毒1（OtHV 1）密切相关，但在没有癌症的海狮生殖道中检测到该病毒，尚未建立因果关系。为了确定OtHV 1是否在引起泌尿生殖器癌中起作用，我们对病毒基因组进行测序，定量来自患有（n = 95）和不患有（n = 163）泌尿生殖器癌的海狮的宫颈组织的病毒载量，并使用原位mRNA杂交（Basescope®）测量病毒mRNA表达以定量和鉴定OtHV 1 mRNA表达的位置。在95只被诊断患有泌尿生殖器癌的海狮中，100%的海狮对OtHV 1呈qPCR阳性，36%的宫颈正常的海狮对病毒呈阳性。非癌性OtHV 1阳性病例的宫颈病毒载量显著低于患有泌尿生殖道癌的海狮的宫颈。OtHV 1基因组有几个基因类似于已知的癌基因，RNA原位杂交显示高OtHV 1 mRNA表达的癌病变内，但不是在正常宫颈上皮。高病毒载量，高表达的OtHV 1在宫颈肿瘤，和可疑的OtHV 1癌基因的存在下支持的假设，OtHV 1在海狮泌尿生殖道癌的发展中起着重要的作用。
Wild California sea lions (Zalophus californianus) have a high prevalence of urogenital carcinoma. The cancer starts in the sea lion’s genital tract then spreads aggressively to other organs resulting in death. Previous research has identified a herpesvirus, otarine herpesvirus 1 (OtHV1), in the genital tract of most sea lions with urogenital carcinoma, however, this virus has also been found in the genital tracts of sea lions without cancer making its role in urogenital carcinoma ambiguous. Here, tissues from 95 sea lions with and 163 without cancer were tested for OtHV1, the amount of virus was quantified, and viral gene expression was measured. OtHV1 was found in 100% of the sea lions with urogenital carcinoma and there were exceptionally high viral loads and viral gene expression within the genital tumors. Of the sea lions that did not have cancer, 36% tested positive for herpesvirus and they had much lower viral load and no detectable viral gene expression, indicating the herpesvirus was dormant. These findings support that genital herpesvirus plays an integral role in sea lion urogenital carcinoma and suggests there is an underlying trigger or event that causes the virus to induce cancer in some infected sea lions and not others. Urogenital carcinoma in California sea lions (Zalophus californianus) is the most common cancer of marine mammals. Primary tumors occur in the cervix, vagina, penis, or prepuce and aggressively metastasize resulting in death. This cancer has been strongly associated with a sexually transmitted herpesvirus, otarine herpesvirus 1 (OtHV1), but the virus has been detected in genital tracts of sea lions without cancer and a causative link has not been established. To determine if OtHV1 has a role in causing urogenital carcinoma we sequenced the viral genome, quantified viral load from cervical tissue from sea lions with (n = 95) and without (n = 163) urogenital carcinoma, and measured viral mRNA expression using in situ mRNA hybridization (Basescope®) to quantify and identify the location of OtHV1 mRNA expression. Of the 95 sea lions diagnosed with urogenital carcinoma, 100% were qPCR positive for OtHV1, and 36% of the sea lions with a normal cervix were positive for the virus. The non-cancer OtHV1 positive cases had significantly lower viral loads in their cervix compared to the cervices from sea lions with urogenital carcinoma. The OtHV1 genome had several genes similar to the known oncogenes, and RNA in situ hybridization demonstrated high OtHV1 mRNA expression within the carcinoma lesions but not in normal cervical epithelium. The high viral loads, high mRNA expression of OtHV1 in the cervical tumors, and the presence of suspected OtHV1 oncogenes support the hypothesis that OtHV1 plays a significant role in the development of sea lion urogenital carcinoma.
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