Exploring the mechanisms of carcinogenesis through the aberrant alternative splicing in head and neck cancer

• Project/Area Number: 18K16860
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56050:Otorhinolaryngology-related
• Research Institution: Tokai University
• Principal Investigator: Akihiro Sakai 東海大学, 医学部, 准教授 (20384886)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 選択的スプライシング / 頭頸部癌 / CPSF1 / RNA-Seq / 扁平上皮癌 / RNA-seq

Outline of Final Research Achievements

We investigated the mechanism of carcinogenesis via ASEs in HNC using RNA sequencing and examined. First, we selected candidate genes from splicing-related genes using TCGA data, and examined the phenotypes of the candidate genes using HNC cell lines. As a result, several genes were selected as candidate genes. Next, after creating overexpression and knockdown cell lines, RNA was extracted, and ASEs induced were identified by RNA-Seq analysis. The results showed that splicing-related gene aberrations induced ASEs of many oncogenes. Abnormalities in splicing-related genes induce ASEs in HNC and may be involved in carcinogenesis.

Academic Significance and Societal Importance of the Research Achievements

遺伝子変異以外の発癌機構として遺伝子発現の下流である転写後調節レベルの選択的スプライシングによる発癌機構が明らかになってきている。このスプライシングによる発癌機構が頭頸部癌の発癌に重要な役割を果たしている可能性が十分あると考え今回の研究を行った。本研究によりスプライシング関連遺伝子CPSF1の遺伝子変異は癌関連遺伝子のASEを幅広く誘発し、CPSF1の発現異常は、頭頸部癌においてASEを誘発することにより、発がんに関与している可能性があることが判明した。さらなる研究により頭頸部癌の発癌機構解明、予後向上に貢献できる可能性がある。

Research Products

• [Journal Article] Predicting the radiosensitivity of HPV-negative oropharyngeal squamous cell carcinoma using miR-130b (2021)
  • Author(s): Inoue Hitoshi、Hirasaki Masataka、Kogashiwa Yasunao、Kuba Kiyomi、Ebihara Yasuhiro、Nakahira Mitsuhiko、Sakai Akihiro、Okuda Akihiko、Sugasawa Masashi
  • Journal Title: Acta Oto-Laryngologica Volume: 1 Issue: 6 Pages: 1-6
  • DOI: 10.1080/00016489.2021.1897160
  • Peer Reviewed
• [Journal Article] Computed Tomography to Diagnose Paranasal Sinus Chemical Burns and Tissue Damage: A Case Report (2021)
  • Author(s): Saito Kosuke、Goto Fumiyuki、Sekine Motoki、Yamamoto Hikaru、Kaneda Shoji、Sakai Akihiro、Ebisumoto Koji、Maki Daisuke、Iijima Hiroaki、Yamauchi Mayu、Watanabe Takane、Okami Kenji
  • Journal Title: The Laryngoscope Volume: 2 Issue: 9 Pages: 1-2
  • DOI: 10.1002/lary.29408
  • Peer Reviewed
• [Journal Article] Reciprocal activation of HEY1 and NOTCH4 under SOX2 control promotes EMT in head and neck squamous cell carcinoma (2020)
  • Author(s): Fukusumi Takahito、Guo Theresa、Ren Shuling、Haft Sunny、Liu Chao、Sakai Akihiro、Ando Mizuo、Saito Yuki、Sadat Sayed、Califano Joseph
  • Journal Title: International Journal of Oncology Volume: 58 Issue: 2 Pages: 226-237
  • DOI: 10.3892/ijo.2020.5156
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] HPV E2, E4, E5 drive alternative carcinogenic pathways in HPV positive cancers (2020)
  • Author(s): Ren Shuling、Gaykalova Daria A.、Guo Theresa、Favorov Alexander V.、Fertig Elana J.、Tamayo Pablo、Callejas-Valera Juan Luis、Allevato Mike、Gilardi Mara、Santos Jessica、Fukusumi Takahito、Sakai Akihiro、et al.
  • Journal Title: Oncogene Volume: 39 Issue: 40 Pages: 6327-6339
  • DOI: 10.1038/s41388-020-01431-8
  • Peer Reviewed
• [Journal Article] Aberrant expression of CPSF1 promotes head and neck squamous cell carcinoma via regulating alternative splicing (2020)
  • Author(s): Sakai Akihiro、Ando Mizuo、Fukusumi Takahito、Ren Shuling、Liu Chao、Qualliotine Jesse、Haft Sunny、Sadat Sayed、Saito Yuki、Guo Theresa W.、Xu Guorong、Sasik Roman、Fisch Kathleen M.、Gutkind J. Silvio、Fertig Elana J.、Molinolo Alfredo A.、Califano Joseph A.
  • Journal Title: PLOS ONE Volume: 15 Issue: 5 Pages: e0233380-e0233380
  • DOI: 10.1371/journal.pone.0233380
  • Peer Reviewed
• [Journal Article] The clinicopathological significance of the adipophilin and fatty acid synthase expression in salivary duct carcinoma. (2020)
  • Author(s): Hirai H、Tada Y、Nakaguro M、Kawakita D、Sato Y、Shimura T、Tsukahara K、Kano S、Ozawa H、Okami K、Sato Y、Fushimi C、Shimizu A、Okamoto I、Takase S、Okada T、Sato H、Imanishi Y、Otsuka K、Watanabe Y、Sakai A、Ebisumoto K、Togashi T、Ueki Y、Ota H、Saigusa N、Takahashi H、Ando M、Urano M、Hanazawa T、Nagao T
  • Journal Title: Virchows Arch Volume: X Issue: 2 Pages: 291-299
  • DOI: 10.1007/s00428-020-02777-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cannabinoids promote progression of HPV positive head and neck squamous cell carcinoma via p38 MAPK activation (2020)
  • Author(s): Liu Chao、Sadat Sayed H、Ebisumoto Koji、Sakai Akihiro、Panuganti Bharat A、Ren Shuling、Goto Yusuke、Haft Sunny、Fukusumi Takahito、Ando Mizuo、Saito Yuki、Guo Theresa、Tamayo Pablo、Yeerna Huwate、Kim William、Hubbard Jacqueline、Sharabi Andrew B、Gutkind J. Silvio、Califano Joseph A.
  • Journal Title: Clinical Cancer Research Volume: - Issue: 11 Pages: 2693-2703
  • DOI: 10.1158/1078-0432.ccr-18-3301
  • Peer Reviewed / Open Access
• [Journal Article] Rational genomic optimization of DNA detection for human papillomavirus type 16 in head and neck squamous cell carcinoma (2020)
  • Author(s): Saito Y, Favorov AV, Forman M, Ren S, Sakai A, Fukusumi T, Liu C, Sadat S, Ando M, Xu G, Khan Z, Pang J, Valsamakis A, Fisch KM, Califano JA.
  • Journal Title: Head & Neck Volume: 42 Issue: 4 Pages: 688-697
  • DOI: 10.1002/hed.26041
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Prognostic Implication of Histopathologic Indicators in Salivary Duct Carcinoma (2020)
  • Author(s): Nakaguro Masato、Sato Yukiko、Tada Yuichiro、Kawakita Daisuke、Nagao Toshitaka et al.
  • Journal Title: The American Journal of Surgical Pathology Volume: 44 Issue: 4 Pages: 526-535
  • DOI: 10.1097/pas.0000000000001413
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A novel splice variant of LOXL2 promotes progression of human papillomavirus?negative head and neck squamous cell carcinoma (2019)
  • Author(s): Liu Chao、Guo Theresa、Sakai Akihiro、Ren Shuling、Fukusumi Takahito、Ando Mizuo、Sadat Sayed、Saito Yuki、Califano Joseph A.
  • Journal Title: Cancer Volume: 126 Issue: 4 Pages: 737-748
  • DOI: 10.1002/cncr.32610
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Evaluation of Nasal Airflow and Resistance: Computational Modeling for Experimental Measurements. (2019)
  • Author(s): Kaneda S, Iida M, Yamamoto H, Sekine M, Ebisumoto K, Sakai A, Takakura Y.
  • Journal Title: Tokai J Exp Clin Med Volume: 44 Pages: 59-67
  • Peer Reviewed / Open Access
• [Journal Article] Chromatin dysregulation and DNA methylation at transcription start sites associated with transcriptional repression in cancers (2019)
  • Author(s): Ando Mizuo、Saito Yuki、et al.
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 2188-2188
  • DOI: 10.1038/s41467-019-09937-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mutation of chromatin regulators and focal hotspot alterations characterize human papillomavirus?positive oropharyngeal squamous cell carcinoma (2019)
  • Author(s): Haft Sunny、Ren Shuling、Xu Guorong、Mark Adam、Fisch Kathleen、Guo Theresa W.、Khan Zubair、Pang John、Ando Mizuo、Liu Chao、Sakai Akihiro、Fukusumi Takahito、Califano Joseph A.
  • Journal Title: Cancer Volume: 125 Issue: 14 Pages: 2423-2434
  • DOI: 10.1002/cncr.32068
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] How to improve the endoscopic view of the hypopharynx: Validation of our novel modified Killian's Method to expose the hypopharynx in 20 subjects (2018)
  • Author(s): Sakai A.、Okami K.、Ebisumoto K.、Yamamoto H.、Saito K.、Maki D.、Furuya H.、Iida M.
  • Journal Title: Clinical Otolaryngology Volume: 43 Issue: 5 Pages: 1407-1410
  • DOI: 10.1111/coa.13172
  • Peer Reviewed
• [Journal Article] Discovery and development of differentially methylated regions in human papillomavirus-related oropharyngeal squamous cell carcinoma (2018)
  • Author(s): Ren Shuling、Gaykalova Daria、Wang Jennifer、Guo Theresa、Danilova Ludmila、Favorov Alexander、Fertig Elana、Bishop Justin、Khan Zubair、Flam Emily、Wysocki Piotr T.、DeJong Peter、Ando Mizuo、Liu Chao、Sakai Akihiro、Fukusumi Takahito、Haft Sunny、Sadat Sayed、Califano Joseph A.
  • Journal Title: International Journal of Cancer Volume: 143 Issue: 10 Pages: 2425-2436
  • DOI: 10.1002/ijc.31778
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The high expression of FOXA1 is correlated with a favourable prognosis in salivary duct carcinomas: a study of 142 cases (2018)
  • Author(s): Urano Makoto、Hirai Hideaki、Tada Yuichiro、Otsuka Kuninori、Watanabe Yoshihiro、Sakai Akihiro、Ebisumoto Koji、Togashi Takafumi、Ueki Yushi、Ota Hisayuki、Sato Yukiko、Saigusa Natsuki、Nakaguro Masato、Hanazawa Toyoyuki、Nagao Toshitaka
  • Journal Title: Histopathology Volume: 73 Issue: 6 Pages: 943-952
  • DOI: 10.1111/his.13706
  • Peer Reviewed / Open Access
• [Journal Article] Characterization of Alternative Splicing Events in HPV-Negative Head and Neck Squamous Cell Carcinoma Identifies an Oncogenic DOCK5 Variant (2018)
  • Author(s): Liu Chao、Guo Theresa、Xu Guorong、Sakai Akihiro、Ren Shuling、Fukusumi Takahito、Ando Mizuo、Sadat Sayed、Saito Yuki、Khan Zubair、Fisch Kathleen M.、Califano Joseph
  • Journal Title: Clinical Cancer Research Volume: 20 Issue: 20 Pages: 5123-5132
  • DOI: 10.1158/1078-0432.ccr-18-0752
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Chronological Progression of an Enlarged Styloid Process: A Case Report of Eagle Syndrome (2018)
  • Author(s): Maki Daisuke、Okami Kenji、Ebisumoto Koji、Sakai Akihiro
  • Journal Title: Case Reports in Otolaryngology Volume: 2018 Pages: 1-4
  • DOI: 10.1155/2018/9207264
• [Presentation] 頭頸部癌における選択的スプライシングを介した発癌機構の解明 (2019)
  • Author(s): 酒井昭博
  • Organizer: 第42回 頭頚部癌学会