The role of SMAD4 expression in carcinogenesis and therapeutic resistance of oral cancer

• Project/Area Number: 19K21413
• Project/Area Number (Other): 18H06329 (2018)
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund (2019); Single-year Grants (2018)
• Review Section: 0907:Oral science and related fields
• Research Institution: Kumamoto University
• Principal Investigator: Sakata Junki 熊本大学, 病院, 医員 (70823326)
• Project Period (FY): 2018-08-24 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 口腔癌 / 治療抵抗性 / SMAD4 / 発癌 / 口腔白板症 / 抗癌剤抵抗性

Outline of Research at the Start

SMAD4発現と白板症の癌化との関連性を明らかにするため、口腔白板症臨床検体を対象として各種免疫組織化学染色を駆使して検討を行う。また口腔上皮細胞株のSMAD4発現を抑制し、各種遺伝子の変化を確認する。また当科で樹立した高転移株、抗癌剤耐性株を用いてSMAD4を抑制させて細胞の遊走・浸潤能の評価を、種々の抗癌剤を用いた薬剤感受性試験で抗癌剤感受性の評価を行う。その形質の変化に関連する分子機構に関しては、SMAD4を抑制した細胞株にて網羅的な遺伝子発現解析を行って関連する遺伝子を探索し、分子メカニズムの解明を行う。

Outline of Final Research Achievements

In the present study, we investigated SMAD4 expression status in biopsy specimens from patients with oral squamous cell carcinoma (OSCC) using immunohistochemical analysis and found that the low SMAD4 expression significantly correlates with poor response to preoperative chemoradiotherapy. Furthermore, we demonstrated that SMAD4 is associated with chemoresistance by activating anti-apoptotic effects via overexpression of cIAP2 in OSCC cells. Therefore, our data indicate that SMAD4 could be useful as a therapeutic biomarker of OSCC. Therapies targeting the SMAD4-dependent anti-apoptotic effects combined with chemotherapy could represent a promising new approach for overcoming chemotherapeutic resistance in OSCC, thereby improving the survival rate.

Academic Significance and Societal Importance of the Research Achievements

口腔扁平上皮癌（OSCC）は口腔癌の80％以上を占める悪性腫瘍であり、近年、OSCCの診断・治療法の選択肢は広がっているが、その5年生存率に大きな改善はみられない。また、わが国での口腔癌および咽頭癌による年間死亡者数は過去15年で約1.5倍に増加しており、その増加傾向の抑制が急務とされる。本研究の成果としてSMAD4が口腔白板症からの癌化予測因子、OSCCの治療効果予測因子および治療標的として応用できる可能性が示唆された。

Research Products

• [Journal Article] Enhanced Expression of IGFBP-3 Reduces Radiosensitivity and Is Associated with Poor Prognosis in Oral Squamous Cell Carcinoma (2020)
  • Author(s): Sakata J, Hirosue A, Yoshida R, Matsuoka Y, Kawahara K, Arita H, Nakashima H, Yamamoto T, Nagata M, Kawaguchi S, Gohara S, Nagao Y, Yamana K, Toya R, Murakami R, Kuwahara Y, Fukumoto M, Nakayama H
  • Journal Title: Cancers (Basel) Volume: 12(2) Issue: 2 Pages: 494-494
  • DOI: 10.3390/cancers12020494
  • Peer Reviewed / Open Access
• [Journal Article] FOXP3 lymphocyte status may predict the risk of malignant transformation in oral leukoplakia (2020)
  • Author(s): Sakata Junki、Yoshida Ryoji、Matsuoka Yuichiro、Kawahara Kenta、Arita Hidetaka、Nakashima Hikaru、Hirosue Akiyuki、Naito Hisaki、Takeshita Hisashi、Kawaguchi Sho、Gohara Shunsuke、Nagao Yuka、Yamana Keisuke、Hiraki Akimitsu、Shinohara Masanori、Ito Takaaki、Nakayama Hideki
  • Journal Title: Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology Volume: 32 Issue: 1 Pages: 33-39
  • DOI: 10.1016/j.ajoms.2019.06.005
  • Peer Reviewed / Open Access
• [Journal Article] HMGA2 Contributes to Distant Metastasis and Poor Prognosis by Promoting Angiogenesis in Oral Squamous Cell Carcinoma. (2019)
  • Author(s): Sakata J,Hirosue A,Yoshida R,Kawahara K,Matsuoka Y,Yamamoto T,Nakamoto M,Hirayama M,Takahashi N,Nakamura T,Arita H,Nakashima H,Nagata M,Hiraki A,Shinohara M,Nakayama H
  • Journal Title: International journal of molecular sciences Volume: 20 Issue: 10 Pages: 2473-2473
  • DOI: 10.3390/ijms20102473
  • Peer Reviewed / Open Access
• [Journal Article] Circulating miRNA-1290 as a potential biomarker for response to chemoradiotherapy and prognosis of patients with advanced oral squamous cell carcinoma: A single-center retrospective study (2019)
  • Author(s): Nakashima H, Yoshida R, Hirosue A, Kawahara K, Sakata J, Arita H, Yamamoto T, Toya R, Murakami R, Hiraki A, Shinohara M, Ito T, Kuwahara Y, Nakayama H
  • Journal Title: Tumour Biol Volume: 41(3) Issue: 3 Pages: 1-10
  • DOI: 10.1177/1010428319826853
  • Peer Reviewed / Open Access
• [Journal Article] Reliability of MRI-Derived Depth of Invasion of Oral Tongue Cancer (2019)
  • Author(s): Murakami Ryuji、Shiraishi Shinya、Yoshida Ryoji、Sakata Junki、Yamana Keisuke、Hirosue Akiyuki、Uchiyama Yoshikazu、Nakayama Hideki、Yamashita Yasuyuki
  • Journal Title: Academic Radiology Volume: 印刷中 Issue: 7 Pages: 30423-9
  • DOI: 10.1016/j.acra.2018.08.021
  • Peer Reviewed / Open Access
• [Presentation] SMAD4の発現低下は口腔白板症の癌化および口腔扁平上皮癌の抗アポトーシス作用を介した抗癌剤抵抗性に関与する (2019)
  • Author(s): 坂田純基、吉田遼司、廣末晃之、川原健太、松岡祐一郎、有田英生、中嶋光、川口翔、竹下尚志、中山秀樹
  • Organizer: 第73回NPO法人日本口腔科学会学術集会