Narisawa-Saito M, Kiyono TBasic mechanisms of high-risk human papillomavirus-induced carcinogenesis: roles of E6 and E7 proteins. Cancer Sci 98: 1505-1511

Virology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Cancer Science (Impact Factor: 3.52). 11/2007; 98(10):1505-11. DOI: 10.1111/j.1349-7006.2007.00546.x
Source: PubMed

ABSTRACT Human papillomaviruses (HPV) are believed to be the primary causal agents for development of pre-neoplastic and malignant lesions of the uterine cervix, and high-risk types such as type 16 and 18 are associated with more than 90% of all cervical carcinomas. The E6 and E7 genes of HPV are thought to play causative roles, since E6 promotes the degradation of p53 through its interaction with E6AP, an E3 ubiquitin ligase, whereas E7 binds to the retinoblastoma protein (pRb) and disrupts its complex formation with E2F transcription factors. Although prophylactic vaccines have become available, it is still necessary to clarify the mechanisms of HPV-induced carcinogenesis because of the widespread nature of HPV infection. Approximately 493,000 new cases of cervical cancer are diagnosed each year with approximately 274,000 mortalities due to invasive cervical cancer. In the present article, the mechanisms of HPV16 E6- and E7-induced multistep carcinogenesis and recently identified functions of these onco-proteins are reviewed.

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Available from: Tohru Kiyono, Sep 01, 2014
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    • "HPV infects basal cells of the cervix through compromised architecture of the mucosa and skin due to sexual activity and is preserved as an episome. Once viral DNA is incorporated into host DNA, oncogenic transformation is induced [32]. An epidemiological study suggests that a biological interaction between HSV-2 and HPV-16 or HPV-18 occurs during the development of cervical carcinoma [33]. "
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    ABSTRACT: Background: miRNAs are a class of small non-coding RNAs that are approximately 21-24 nucleotides in length and regulate gene expression post-transcriptionally by way of translational repression or transcript cleavage. They are undoubtedly dysregulated in several neoplastic events but the discordant reports trailing some of them have limited their application in diagnostic pathology. The aim of this review was to evaluate reports of miRNA dysregulation in cervical cancer in a bid to finding explanation for the discordance and to identify the best diagnostic and prognostic biomarker for cervical cancer. Method: Articles on miRNA expression in cervical cancer were downloaded from journal websites, Google scholar, Pubmed and Researchgate. The MiRNAs were classified using two criteria; 1) Frequency of reports using a scale of: 6-5 for Class I, 4-3 for Class II, 2 for Class III and 1 report for Class IV; 2) status of controversy, which included: Controversial (C) and Uncontroversial (UC). The controversial group was subdivided into Most Controversial (MC; >25%) and Less Controversial (LC; ≤25%). Result: Sixty-six (66) miRNAs were found to be dysregulated in cervical cancers, out of which 9 (13.6%) miRNAs were controversial, 20 (30.3%) miRNAs were uncontroversial and 37 (56.1%) miRNAs are yet to be validated by other reports. Considering frequency of reports, 5 miRNAs (7.7%), 13 miRNAs (20%), 10 miRNAs (15.4%) and 37 (56.9%) were grouped into Class I, II, III and IV, respectively. In all, only 8 (12%) miRNAs (miR-21, miR-18a, miR-20a, miR-29a, miR-25, miR-183, miR-196a, miR-218) were found to be most reported and without controversy. Conclusions: the expression of miRNAs is affected by overlapping factors such as cancer stage, type of sample analyzed, technique employed, type of viral agent and oncoprotein present. In is important that this factors be considered prior to sample analysis. Since miR-21 is more frequently reported without any discordance when compared with other miRNAs, it should be adopted as the best biomarker in monitoring and management of cervical cancer patients.
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    • "Low expression of p130 and p107 or inactivated APC frequently occurs in the carcinogenic processes of multiple types of cancers [72] [73]. Both high expressions of FOXM1 and E7 are important risk factors for tumorigenesis [74] [75]. Thus elevated NEK2A in cancer cells may be induced by those abnormal conditions. "
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    ABSTRACT: Chromosome instability (CIN) has been identified as a common feature of most human cancers. A number of centrosomal kinases are thought to cause CIN in cancer cells. Part of those centrosomal kinases exhibit elevated expression in a wide variety of tumours and cancer cell lines. Additionally, critical roles in many aspects of cancer cell growth, proliferation, metastasis, and drug resistance have been assigned to some of these centrosomal kinases, such as polo-like kinase 1 (PLk1) and Aurora-A kinase. Recent studies from our group and others revealed that a centrosomal kinase, Never in Mitosis (NIMA) Related Kinase 2A (NEK2A), is frequently upregulated in multiple types of human cancers. Uncontrolled activity of NEK2A activates several oncogenic pathways and ABC transporters, thereby leading to CIN, cancer cell proliferation, metastasis, and enhanced drug resistance. In this paper, we highlight recent findings on the aberrant expression and functional significance of NEK2A in human cancers and emphasize their significance for therapeutic potentials.
    02/2015; 2015:1-12. DOI:10.1155/2015/862461
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    • "In vitro treatment with Tan IIA markedly inhibited cervical cancer cell proliferation in HPV-positive, CaSki, HeLa, SiHa and HPV-negative C33a cells. HPV E6 and E7 oncoproteins exert profound effects on tumor suppressor proteins p53 and pRb, respectively, by accelerating their ubiquitin-mediated degradation [31] [32]. Most primary cervical cancers and cancer cell lines are known to harbor wild-type p53 and p105Rb genes [33] [34]. "
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    ABSTRACT: Human papilloma virus (HPV) is the well-established etiological factor of cervical cancer. E6 and E7 oncoproteins expressed by HPV are known to inactivate tumor suppressor proteins p53 and pRb, respectively. Tanshinone IIA (Tan IIA) is a diterpenoid naphthoquinone found in the traditional Chinese medicine Danshen (Salvia sp). Tan IIA has been shown to possess anti-tumor activity against several cancer types. In this study we show that Tan IIA potently inhibited proliferation of the human cervical cancer cells CaSki, SiHa, HeLa and C33a. Mechanistically in HPV positive CaSki cells, Tan IIA was found to i) downregulate expression of HPV E6 and E7 genes and modulate associated proteins E6AP and E2F1, ii) cause S phase cell cycle arrest, iii) induce accumulation of p53 and alter expression of p53-dependent targets, iv) modulate pRb and related proteins, and v) cause p53-mediated apoptosis by moderating Bcl2, Bax, caspase-3, and PARP cleavage expressions. In vivo, Tan IIA resulted in over 66% reduction in tumor volume of cervical cancer xenograft in athymic nude mice. Tan IIA treated tumor tissues had lower expression of proliferation marker PCNA and changes in apoptosis targets were in agreement with in vitro studies, further confirming reduced proliferation and involvement of multiple targets behind anti-cancer effects. This is the first demonstration of Tan IIA to possess significant anti-viral activity by repressing of HPV oncogenes leading to inhibition of cervical cancer. Together, our data suggest that Tan IIA can be exploited as a potent therapeutic agent for the prevention and treatment of cervical and other HPV-related cancers.
    Cancer Letters 10/2014; 356(2). DOI:10.1016/j.canlet.2014.09.037 · 5.62 Impact Factor
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