遺伝子診療研究部

がんの新しいマーカーを見つける研究をします。
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研究内容・課題

研究内容(目的)

がん細胞は、正常な細胞ではほとんど見られない特殊な物質を作ることがあります。このがんにより大量につくられた特殊な物質が血液中に出現してきたものを「腫瘍マーカー」といいます。腫瘍マーカーは、(1)がんの早期発見、(2)がん診断の補助的な検査、(3)治療効果判定(4)再発の早期発見に使われます。

私たちは、がんを詳細に解析し、がんで作られる特殊な物質(腫瘍マーカー)を探索し、同定しています。さらに、その物質の血液や尿での濃度を測定できるようにし、患者さんにとって診断や治療に伴う身体的苦痛が少ない検査法を開発します。

研究課題(目的を達成するための方法)

(1) プロジェクトHOPE(がんのマルチオミクス解析)

がん組織と正常組織について網羅的に遺伝子の発現解析を行っています(全遺伝子発現解析;トランスクリプトミクス)。がんでどのようは遺伝子が発現しているか、または発現していないかという情報は、がんの病態解明につながります。

(2) 腫瘍マーカー 新規腫瘍マーカーの同定

培養がん細胞やプロジェクトHOPEで解析したがん組織について、がんで作られている特殊な物質(RNAやタンパク質)を解析し、腫瘍マーカー候補を見つけます。採血等の低侵襲な方法により検出可能な測定系の開発を行います。

(3) 腫瘍マーカー 新規がん-胎児タンパク質の同定

実験動物管理室と共同で、胎児タンパク質が腫瘍マーカーにならないか検討しています。

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研究スタッフ

遺伝子診療研究部 部長 望月 徹(もちづき とおる)

51001 E-mail  t.mochizukiscchr
専門分野 プロテオミクスによる腫瘍マーカーの探索、ペプチド化学

 

遺伝子診療研究部 部長代理 大島 啓一(おおしま けいいち)

51002 E-mail k.ohshimascchr
専門分野 遺伝子発現解析、タンパク質・ペプチドやマイクロRNAを対象とした細胞外分泌成分(セクレトーム)の解析

 

遺伝子診療研究部 主任研究員 畠山 慶一(はたけやま けいいち)

51003 E-mail k.hatakeyamascchr
専門分野 スプライスバリアントを対象とした遺伝子発現とプロテオーム解析、微小流体技術を利用した単一細胞解析

 

遺伝子診療研究部 非常勤研究員 佐倉 直樹(さくら なおき)

51004 E-mail n.sakurascchr
専門分野 ペプチド合成化学、タンパク質の特異的・高感度検出法の開発、生理活性ペプチドの構造-活性相関

 

遺伝子診療研究部 技術員 渡辺 ゆう子
遺伝子診療研究部 技術員 井出 智美
遺伝子診療研究部 技術員 諸見里 幸

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研究成果

論文

1. Ashida R, Okamura Y, Ohshima K, Kakuda Y, Uesaka K, Sugiura T, Ito T, Yamamoto Y, Sugino T, Urakami K, Kusuhara M, Yamaguchi K. CYP3A4 Gene Is a Novel Biomarker for Predicting a Poor Prognosis in Hepatocellular Carcinoma. Cancer Genomics Proteomics. 2017 Nov-Dec;14(6):445-453. PubMed PMID: 29109094.

2. Naruoka A, Ohnami S, Nagashima T, Serizawa M, Ohshima K, Ohnami S, Urakami K, Horiuchi Y, Kiyozumi Y, Abe M, Nakajima T, Sugiura T, Uesaka K, Kusuhara M, Yamaguchi K. Germline and somatic genetic changes in multicentric tumors obtained from a patient with multiple endocrine neoplasia type 1. Hum Genome Var. 2017 Apr 27;4:17013. doi: 10.1038/hgv.2017.13. eCollection 2017. PubMed PMID: 28503312; PubMed Central PMCID: PMC5406389.

3. Kiyohara Y, Yoshikawa S, Otsuka M, Kondou R, Iizuka A, Nonomura C, Ohshima K, Urakami K, Kusuhara M, Nagashima T, Sugino T, Yamaguchi K, Akiyama Y. Melanoma patient response to nivolumab treatment for metastatic lung lesions: Multi-OMICS analysis in Project HOPE. J Dermatol. 2017 Oct;44(10):1156-1159. doi: 10.1111/1346-8138.13879. Epub 2017 Apr 28. PubMed PMID: 28452169.

4. Ohshima K, Hatakeyama K, Nagashima T, Watanabe Y, Kanto K, Doi Y, Ide T, Shimoda Y, Tanabe T, Ohnami S, Ohnami S, Serizawa M, Maruyama K, Akiyama Y, Urakami K, Kusuhara M, Mochizuki T, Yamaguchi K. Integrated analysis of gene expression and copy number identified potential cancer driver genes with amplification-dependent overexpression in 1,454 solid tumors. Sci Rep. 2017 Apr 4;7(1):641. doi: 10.1038/s41598-017-00219-3. PubMed PMID: 28377632; PubMed Central PMCID: PMC5428069.

5. Yoshikawa S, Kiyohara Y, Otsuka M, Kondou R, Nonomura C, Miyata H, Iizuka A, Ohshima K, Urakami K, Nagashima T, Kusuhara M, Sugino T, Mochizuki T, Yamaguchi K, Akiyama Y. Multi-omics Profiling of Patients with Melanoma Treated with Nivolumab in Project HOPE. Anticancer Res. 2017 Mar;37(3):1321-1328. PubMed PMID: 28314298.

6. Ohnami S, Ohshima K, Nagashima T, Urakami K, Shimoda Y, Saito J, Naruoka A, Hatakeyama K, Mochizuki T, Serizawa M, Ohnami S, Kusuhara M, Yamaguchi K. Comprehensive characterization of genes associated with the TP53 signal transduction pathway in various tumors. Mol Cell Biochem. 2017 Jul;431(1-2):75-85. doi: 10.1007/s11010-017-2977-1. Epub 2017 Mar 3. PubMed PMID: 28258440; PubMed Central PMCID: PMC5487743.

7. Yamakawa Y, Kusuhara M, Terashima M, Kinugasa Y, Sugino T, Abe M, Mochizuki T, Hatakeyama K, Kami K, Yamaguchi K. CD44 variant 9 expression as a predictor for gastric cancer recurrence: immunohistochemical and metabolomic analysis of surgically resected tissues. Biomed Res. 2017;38(1):41-52. doi: 10.2220/biomedres.38.41. PubMed PMID: 28239031.

8. Makuuchi R, Terashima M, Kusuhara M, Nakajima T, Serizawa M, Hatakeyama K, Ohshima K, Urakami K, Yamaguchi K. Comprehensive analysis of gene mutation and expression profiles in neuroendocrine carcinomas of the stomach. Biomed Res. 2017;38(1):19-27. doi: 10.2220/biomedres.38.19. PubMed PMID: 28239029.

9. Ide T, Sakura N, Wakabayashi-Nakao K, Ohshima K, Hatakeyama K, Ogura S, Mochizuki T. Development of high specific and sensitive proglucagon (ProGL)-ELISA systems. Peptide Science 2015, p.227-230, 2016.

10. Shimoda Y, Nagashima T, Urakami K, Tanabe T, Saito J, Naruoka A, Serizawa M, Mochizuki T, Ohshima K, Ohnami S, Ohnami S, Kusuhara M, Yamaguchi K. Integrated next-generation sequencing analysis of whole exome and 409 cancer-related genes. Biomed Res. 2016;37(6):367-379. doi: 10.2220/biomedres.37.367. PubMed PMID: 28003584.

11. Nagashima T, Shimoda Y, Tanabe T, Naruoka A, Saito J, Serizawa M, Ohshima K, Urakami K, Ohnami S, Ohnami S, Mochizuki T, Kusuhara M, Yamaguchi K. Optimizing an ion semiconductor sequencing data analysis method to identify somatic mutations in the genomes of cancer cells in clinical tissue samples. Biomed Res. 2016;37(6):359-366. doi: 10.2220/biomedres.37.359. PubMed PMID: 28003583.

12. Iizuka A, Kondou R, Nonomura C, Ashizawa T, Ohshima K, Kusuhara M, Isaka M, Ohde Y, Yamaguchi K, Akiyama Y. Unstable B7-H4 cell surface expression and T-cell redirection as a means of cancer therapy. Oncol Rep. 2016 Nov;36(5):2625-2632. doi: 10.3892/or.2016.5084. Epub 2016 Sep 12. PubMed PMID: 27632942.

13. Yamaguchi K, Urakami K, Nagashima T, Shimoda Y, Ohnami S, Ohnami S, Ohshima K, Mochizuki T, Hatakeyama K, Serizawa M, Akiyama Y, Maruyama K, Katagiri H, Ishida Y, Takahashi K, Nishimura S, Terashima M, Kawamura T, Kinugasa Y, Yamakawa Y, Onitsuka T, Ohde Y, Sugino T, Ito I, Matsubayashi H, Horiuchi Y, Mizuguchi M, Yamazaki M, Inoue K, Wakamatsu K, Sugiyama M, Uesaka K, Kusuhara M. Prevalence of low-penetrant germline TP53 D49H mutation in Japanese cancer patients. Biomed Res. 2016;37(4):259-64. doi: 10.2220/biomedres.37.259. PubMed PMID: 27545002.

14. Akiyama Y, Kondou R, Iizuka A, Ohshima K, Urakami K, Nagashima T, Shimoda Y, Tanabe T, Ohnami S, Ohnami S, Kusuhara M, Mochizuki T, Yamaguchi K. Immune response-associated gene analysis of 1,000 cancer patients using whole-exome sequencing and gene expression profiling-Project HOPE. Biomed Res. 2016;37(4):233-42. doi: 10.2220/biomedres.37.233. PubMed PMID: 27544999.

15. Serizawa M, Kusuhara M, Ohnami S, Nagashima T, Shimoda Y, Ohshima K, Mochizuki T, Urakami K, Yamaguchi K. Novel Tumor-specific Mutations in Receptor Tyrosine Kinase Subdomain IX Significantly Reduce Extracellular Signal-regulated Kinase Activity. Anticancer Res. 2016 Jun;36(6):2733-44. PubMed PMID: 27272783.

16. Urakami K, Shimoda Y, Ohshima K, Nagashima T, Serizawa M, Tanabe T, Saito J, Usui T, Watanabe Y, Naruoka A, Ohnami S, Ohnami S, Mochizuki T, Kusuhara M, Yamaguchi K. Next generation sequencing approach for detecting 491 fusion genes from human cancer. Biomed Res. 2016;37(1):51-62. doi: 10.2220/biomedres.37.51. PubMed PMID: 26912140.

17. Yamaguchi K, Katagiri H, Takahashi M, Ishida Y, Ono A, Takahashi T, Ohshima K, Mochizuki T, Urakami K, Muramatsu K, Kameya T, Ito I, Nakajima T. ProGRP is a possible tumor marker for patients with Ewing sarcoma. Biomed Res. 2015;36(4):273-7. doi: 10.2220/biomedres.36.273. PubMed PMID: 26299486.

18. Sakura N, Ide T, Wakabayashi-Nakao K, Ohshima K, Hatakeyama K, Ogura S, Mochizuki T. Identification of proglucagon (proGL) secreted from a duodenal cancer cell line. Peptide Science 2014, p.253-256, 2015.

19. Hatakeyama K, Yamakawa Y, Fukuda Y, Ohshima K, Wakabayashi-Nakao K, Sakura N, Tanizawa Y, Kinugasa Y, Yamaguchi K, Terashima M, Mochizuki T. A novel splice variant of XIAP-associated factor 1 (XAF1) is expressed in peripheral blood containing gastric cancer-derived circulating tumor cells. Gastric Cancer. 2014 Sep 13. [Epub ahead of print] PubMed PMID: 25216542.

20. Sakura N, Ide T, Wakabayashi-Nakao K, Ohshima K, Hatakeyama K, Ogura S, Mochizuki T. Synthesis of proneurotensin/neuromedin N (proNT/NMN) N-terminal-related peptides to develop a proNT/NMN-specific ELISA system. Peptide Science 2013, p.207-210, 2014.

21. Wakabayashi-Nakao K, Hatakeyama K, Ohshima K, Ken Yamaguchi K, Mochizuki T. Carcinoembryonic antigen-related cell adhesion molecule 4 (CEACAM4) is specifically expressed in medullary thyroid carcinoma cells. Biomed Res. 2014;35(4):237-42. PubMed PMID: 25152032.

22. Ohshima K, Kanto K, Hatakeyama K, Ide T, Wakabayashi-Nakao K, Watanabe Y, Sakura N, Terashima M, Yamaguchi K, Mochizuki T. Exosome-mediated extracellular release of polyadenylate-binding protein 1 in human metastatic duodenal cancer cells. Proteomics. 2014 Oct;14(20):2297-306. doi: 10.1002/pmic.201300477. Epub 2014 Sep 1. PubMed PMID: 25065644.

23. Yamaguchi K, Urakami K, Ohshima K, Mochizuki T, Akiyama Y, Uesaka K, Nakajima T, Takahashi M, Tamai S, Kusuhara M. Implementation of individualized medicine for cancer patients by multiomics-based analyses—the Project HOPE—. Biomed Res. 2014;35(6):407-12. doi: 10.2220/biomedres.35.407. PubMed PMID: 25743347.

24. Hatakeyama K, Wakabayashi-Nakao K, Ohshima K, Sakura N, Yamaguchi K, Mochizuki T. Novel protein isoforms of carcinoembryonic antigen are secreted from pancreatic, gastric and colorectal cancer cells. BMC Res Notes. 2013 Sep 26;6:381. doi: 10.1186/1756-0500-6-381. PubMed PMID: 24070190; PubMed Central PMCID: PMC3850884.

25. Hatakeyama K, Fukuda Y, Ohshima K, Terashima M, Yamaguchi K, Mochizuki T. Placenta-specific novel splice variants of Rho GDP dissociation inhibitor β are highly expressed in cancerous cells. BMC Res Notes. 2012 Dec 3;5:666. doi: 10.1186/1756-0500-5-666. PubMed PMID: 23206989; PubMed Central PMCID: PMC3554444.

26. Wakabayashi-Nakao K, Maruyama K, Ishii H, Muramatsu K, Hatakeyama K, Ohshima K, Ogura S, Nakajima T, Yamaguchi K, Mochizuki T. Investigation of proNT/NMN secretion from small cell lung carcinoma cells using a mouse xenograft model. Oncol Rep. 2012 Oct;28(4):1181-6. doi: 10.3892/or.2012.1926. Epub 2012 Jul 23. PubMed PMID: 22825476.

27. Ohshima K, Takeda S, Hirose M, Akiyama Y, Iguchi K, Hoshino M, Yamaguchi K, Mochizuki T. Structure-function relationship of the nuclear localization signal sequence of parathyroid hormone-related protein. Biomed Res. 2012 Jun;33(3):191-9. PubMed PMID: 22790219.

28. Hatakeyama K, Wakabayashi-Nakao K, Aoki Y, Ogura S, Yamaguchi K, Nakajima T, Sato TA, Mochizuki T, Hayashi I. Novel protein extraction approach using micro-sized chamber for evaluation of proteins eluted from formalin-fixed paraffin-embedded tissue sections. Proteome Sci. 2012 Mar 23;10:19. doi: 10.1186/1477-5956-10-19. PubMed PMID: 22439923; PubMed Central PMCID: PMC3352043.

29. Hatakeyama K, Ohshima K, Fukuda Y, Ogura S, Terashima M, Yamaguchi K, Mochizuki T. Identification of a novel protein isoform derived from cancer-related splicing variants using combined analysis of transcriptome and proteome. Proteomics. 2011 Jun;11(11):2275-82. doi: 10.1002/pmic.201100016. Epub 2011 May 5. PubMed PMID: 21548097.

30. Ohshima K, Inoue K, Fujiwara A, Hatakeyama K, Kanto K, Watanabe Y, Muramatsu K, Fukuda Y, Ogura S, Yamaguchi K, Mochizuki T. Let-7 microRNA family is selectively secreted into the extracellular environment via exosomes in a metastatic gastric cancer cell line. PLoS One. 2010 Oct 8;5(10):e13247. doi: 10.1371/journal.pone.0013247. PubMed PMID: 20949044; PubMed Central PMCID: PMC2951912.

31. Takata H, Nishijima H, Ogura S, Sakaguchi T, Bubulya PA, Mochizuki T, Shibahara K. Proteome analysis of human nuclear insoluble fractions. Genes Cells. 2009 Aug;14(8):975-90. doi: 10.1111/j.1365-2443.2009.01324.x. PubMed PMID: 19695025; PubMed Central PMCID: PMC4158948.

32. Kusafuka K, Bando E, Muramatsu K, Ito H, Tanizawa Y, Kawamura T, Mochizuki T, Terashima M, Nakajima T. Pancreatic-type mixed acinar-endocrine carcinoma with alpha-fetoprotein production arising from the stomach: a report of an extremely rare case. Med Mol Morphol. 2009 Sep;42(3):167-74. doi: 10.1007/s00795-009-0446-y. Epub 2009 Sep 26. PubMed PMID: 19784744.

33. Muramatsu K, Kusafuka K, Watanabe H, Mochizuki T, Nakajima T. Ultrastructural immunolocalization of a cartilage-specific proteoglycan, aggrecan, in salivary pleomorphic adenomas. Med Mol Morphol. 2009 Mar;42(1):47-54. doi: 10.1007/s00795-008-0429-4. Epub 2009 Mar 18. PubMed PMID: 19294492.

34. Ogura S, Kaneko K, Miyajima S, Ohshima K, Yamaguchi K, Mochizuki T. Proneurotensin/neuromedin N secreted from small cell lung carcinoma cell lines as a potential tumor marker. Proteomics Clin Appl. 2008 Dec;2(12):1620-7. doi: 10.1002/prca.200800039. Epub 2008 Nov 14. PubMed PMID: 21136812.

35. Kusafuka K, Muramatsu K, Kasami M, Kuriki K, Hirobe K, Hayashi I, Watanabe H, Hiraki Y, Shukunami C, Mochizuki T, Kameya T. Cartilaginous features in matrix-producing carcinoma of the breast: four cases report with histochemical and immunohistochemical analysis of matrix molecules. Mod Pathol. 2008 Oct;21(10):1282-92. doi: 10.1038/modpathol.2008.120. Epub 2008 Jul 11. PubMed PMID: 18622387.

36. Hagiya Y, Adachi T, Ogura S, An R, Tamura A, Nakagawa H, Okura I, Mochizuki T, Ishikawa T. Nrf2-dependent induction of human ABC transporter ABCG2 and heme oxygenase-1 in HepG2 cells by photoactivation of porphyrins: biochemical implications for cancer cell response to photodynamic therapy. J Exp Ther Oncol. 2008;7(2):153-67. PubMed PMID: 18771089. 

37. Maruyama K, Takeyama H, Mori T, Ohshima K, Ogura S, Mochizuki T, Matsunaga T. Detection of epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) using a fully automated system with a nano-scale engineered biomagnetite. Biosens Bioelectron. 2007 Apr 15;22(9-10):2282-8. Epub 2006 Dec 21. PubMed PMID: 17187977.

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