HPV陽性および陰性の口腔扁平上皮がんに対するin vitro多段階発がんモデル  [in Japanese] An in vitro multistep carcinogenesis model for both HPV-positive and -negative human oral squamous cell carcinomas  [in Japanese]

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Author(s)

    • 頭司 雄介 ZUSHI Yusuke
    • 兵庫医科大学歯科口腔外科学講座 Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine

Abstract

Oral squamous cell carcinomas (OSCCs) are considered to arise from human oral keratinocytes. DNAs of human papillomaviruses (HPVs), predominantly types 16 and 18, etiological agents of cervical cancers, have been detected in approximately 25% of OSCCs. In accordance with the established roles of E6 and E7 in inactivating p53 and pRb, respectively, mutations of p53 and inactivation of p16<sup>INK4a</sup> are frequently observed in HPV-negative OSCCs. In addition, other alterations such as overexpression of epidermal growth factor receptor (EGFR) are often observed in both HPV-positive and -negative OSCCs. However, the causal relation between accumulation of these abnormalities and multistep carcinogenesis is not fully understood. To elucidate underlying processes, we transduced either HPV16 E6/E7 or a mutant CDK4 (CDK4<sup>R24C</sup>), cyclin D1, and human telomerase reverse transcriptase (TERT) into primary human tongue keratinocytes (HTK), and obtained immortal cell populations, HTK-16E6E7 and HTK-K4DT. Additional transduction of oncogenic HR AS or EGFR together with MYC into HTK-16E6E7 and dominant negative p53 expressing HTK-K4DT resulted in anchorage-independent growth and subcutaneous tumor formation in nude mice. These results indicate that either HRAS mutation or activation of EGFR in cooperation with MYC overexpression play critical roles in transformation of HTKs on a background of inactivation of the pRB and p53 pathways and telomerase activation. This in vitro model system recapitulating the development of OSCCs should facilitate further studies of mechanisms of carcinogenesis in the oral cavity.

Oral squamous cell carcinomas (OSCCs) are considered to arise from human oral keratinocytes. DNAs of human papillomaviruses (HPVs), predominantly types 16 and 18, etiological agents of cervical cancers, have been detected in approximately 25% of OSCCs. In accordance with the established roles of E6 and E7 in inactivating p53 and pRb, respectively, mutations of p53 and inactivation of p16<sup>INK4a</sup> are frequently observed in HPV-negative OSCCs. In addition, other alterations such as overexpression of epidermal growth factor receptor (EGFR) are often observed in both HPV-positive and -negative OSCCs. However, the causal relation between accumulation of these abnormalities and multistep carcinogenesis is not fully understood. To elucidate underlying processes, we transduced either HPV16 E6/E7 or a mutant CDK4 (CDK4<sup>R24C</sup>), cyclin D1, and human telomerase reverse transcriptase (TERT) into primary human tongue keratinocytes (HTK), and obtained immortal cell populations, HTK-16E6E7 and HTK-K4DT. Additional transduction of oncogenic HR AS or EGFR together with MYC into HTK-16E6E7 and dominant negative p53 expressing HTK-K4DT resulted in anchorage-independent growth and subcutaneous tumor formation in nude mice. These results indicate that either HRAS mutation or activation of EGFR in cooperation with MYC overexpression play critical roles in transformation of HTKs on a background of inactivation of the pRB and p53 pathways and telomerase activation. This in vitro model system recapitulating the development of OSCCs should facilitate further studies of mechanisms of carcinogenesis in the oral cavity.

Journal

  • Japanese Journal of Oral and Maxillofacial Surgery

    Japanese Journal of Oral and Maxillofacial Surgery 59(3), 159-171, 2013

    Japanese Society of Oral and Maxillofacial Surgeons

Codes

  • NII Article ID (NAID)
    130004707939
  • Text Lang
    JPN
  • ISSN
    0021-5163
  • Data Source
    J-STAGE 
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