Rawla, P., Sunkara, T. & Gaduputi, V. Epidemiology of Pancreatic Cancer: Global
Trends, Etiology and Risk Factors. World Journal of Oncology 10, 10-27, 2019.
Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2020. CA: A Cancer Journal
for Clinicians 70, 7-30, 2020.
Anastasiadou, E., Jacob, L. S. & Slack, F. J. Non-coding RNA networks in cancer.
Nature Reviews Cancer 18, 5-18, 2018.
Ting, D. T., Lipson, D., Paul, S., Brannigan, B. W., Akhavanfard, S., Coffman, E. J.,
Contino, G., Deshpande, V., Iafrate, A. J., Letovsky, S., Rivera, M. N., Bardeesy, N.,
Maheswaran, S. & Haber, D. A. Aberrant overexpression of satellite repeats in
pancreatic and other epithelial cancers. Science 331, 593-596, 2011.
Anfossi, S., Babayan, A., Pantel, K. & Calin, G. A. Clinical utility of circulating
non-coding RNAs - an update. Nature Reviews Clinical Oncology 15, 541-563, 2018.
Kishikawa, T., Otsuka, M., Yoshikawa, T., Ohno, M., Yamamoto, K., Yamamoto, N.,
Kotani, A. & Koike, K. Quantitation of circulating satellite RNAs in pancreatic cancer
patients. JCI Insight 1, e86646-e86646, 2016.
Nigro, J. M., Cho, K. R., Fearon, E. R., Kern, S. E., Ruppert, J. M., Oliner, J. D.,
Kinzler, K. W. & Vogelstein, B. Scrambled exons. Cell 64, 607-613, 1991.
- 59 -
Cocquerelle, C., Daubersies, P., Majérus, M. A., Kerckaert, J. P. & Bailleul, B.
Splicing with inverted order of exons occurs proximal to large introns. The EMBO
Journal 11, 1095-1098, 1992.
Capel, B., Swain, A., Nicolis, S., Hacker, A., Walter, M., Koopman, P., Goodfellow, P.
& Lovell-Badge, R. Circular transcripts of the testis-determining gene Sry in adult
mouse testis. Cell 73, 1019-1030, 1993.
10
Cocquerelle, C., Mascrez, B., Hétuin, D. & Bailleul, B. Mis-splicing yields circular
RNA molecules. FASEB Journal : official publication of the Federation of American
Societies for Experimental Biology 7, 155-160, 1993.
11
Glažar, P., Papavasileiou, P. & Rajewsky, N. circBase: a database for circular RNAs.
RNA 20, 1666-1670, 2014.
12
Vo, J. N., Cieslik, M., Zhang, Y., Shukla, S., Xiao, L., Zhang, Y., Wu, Y. M.,
Dhanasekaran, S. M., Engelke, C. G., Cao, X., Robinson, D. R., Nesvizhskii, A. I. &
Chinnaiyan, A. M. The Landscape of Circular RNA in Cancer. Cell 176, 869-881.e813,
2019.
13
Dong, R., Ma, X. K., Li, G. W. & Yang, L. CIRCpedia v2: An Updated Database for
Comprehensive Circular RNA Annotation and Expression Comparison. Genomics,
Proteomics & Bioinformatics 16, 226-233, 2018.
14
Memczak, S., Jens, M., Elefsinioti, A., Torti, F., Krueger, J., Rybak, A., Maier, L.,
- 60 -
Mackowiak, S. D., Gregersen, L. H., Munschauer, M., Loewer, A., Ziebold, U.,
Landthaler, M., Kocks, C., le Noble, F. & Rajewsky, N. Circular RNAs are a large
class of animal RNAs with regulatory potency. Nature 495, 333-338, 2013.
15
Salzman, J., Chen, R. E., Olsen, M. N., Wang, P. L. & Brown, P. O. Cell-type specific
features of circular RNA expression. PLoS Genetics 9, e1003777, 2013.
16
Suzuki, H., Zuo, Y., Wang, J., Zhang, M. Q., Malhotra, A. & Mayeda, A.
Characterization of RNase R-digested cellular RNA source that consists of lariat and
circular RNAs from pre-mRNA splicing. Nucleic Acids Research 34, e63, 2006.
17
Jeck, W. R., Sorrentino, J. A., Wang, K., Slevin, M. K., Burd, C. E., Liu, J., Marzluff,
W. F. & Sharpless, N. E. Circular RNAs are abundant, conserved, and associated with
ALU repeats. RNA 19, 141-157, 2013.
18
Li, Y., Zheng, Q., Bao, C., Li, S., Guo, W., Zhao, J., Chen, D., Gu, J., He, X. & Huang,
S. Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer
diagnosis. Cell Research 25, 981-984, 2015.
19
Enuka, Y., Lauriola, M., Feldman, M. E., Sas-Chen, A., Ulitsky, I. & Yarden, Y.
Circular RNAs are long-lived and display only minimal early alterations in response to
a growth factor. Nucleic Acids Research 44, 1370-1383, 2016.
20
Hansen, T. B., Jensen, T. I., Clausen, B. H., Bramsen, J. B., Finsen, B., Damgaard, C.
K. & Kjems, J. Natural RNA circles function as efficient microRNA sponges. Nature
- 61 -
495, 384-388, 2013.
21
Hsiao, K. Y., Lin, Y. C., Gupta, S. K., Chang, N., Yen, L., Sun, H. S. & Tsai, S. J.
Noncoding Effects of Circular RNA CCDC66 Promote Colon Cancer Growth and
Metastasis. Cancer Research 77, 2339-2350, 2017.
22
Zheng, Q., Bao, C., Guo, W., Li, S., Chen, J., Chen, B., Luo, Y., Lyu, D., Li, Y., Shi, G.,
Liang, L., Gu, J., He, X. & Huang, S. Circular RNA profiling reveals an abundant
circHIPK3 that regulates cell growth by sponging multiple miRNAs. Nature
Communications 7, 11215, 2016.
23
Verduci, L., Ferraiuolo, M., Sacconi, A., Ganci, F., Vitale, J., Colombo, T., Paci, P.,
Strano, S., Macino, G., Rajewsky, N. & Blandino, G. The oncogenic role of circPVT1
in head and neck squamous cell carcinoma is mediated through the mutant
p53/YAP/TEAD transcription-competent complex. Genome Biology 18, 237, 2017.
24
Kristensen, L. S., Hansen, T. B., Venø, M. T. & Kjems, J. Circular RNAs in cancer:
opportunities and challenges in the field. Oncogene 37, 555-565, 2018.
25
Kristensen, L. S., Andersen, M. S., Stagsted, L. V. W., Ebbesen, K. K., Hansen, T. B.
& Kjems, J. The biogenesis, biology and characterization of circular RNAs. Nature
Reviews Genetics 20, 675-691, 2019.
26
Chen, L. L. The expanding regulatory mechanisms and cellular functions of circular
RNAs. Nature reviews. Molecular Cell Biology 21, 475-490, 2020.
- 62 -
27
Guarnerio, J., Zhang, Y., Cheloni, G., Panella, R., Mae Katon, J., Simpson, M.,
Matsumoto, A., Papa, A., Loretelli, C., Petri, A., Kauppinen, S., Garbutt, C., Nielsen,
G. P., Deshpande, V., Castillo-Martin, M., Cordon-Cardo, C., Dimitrios, S., Clohessy,
J. G., Batish, M. & Pandolfi, P. P. Intragenic antagonistic roles of protein and circRNA
in tumorigenesis. Cell Research 29, 628-640, 2019.
28
Li, Q., Wang, Y., Wu, S., Zhou, Z., Ding, X., Shi, R., Thorne, R. F., Zhang, X. D., Hu,
W. & Wu, M. CircACC1 Regulates Assembly and Activation of AMPK Complex
under Metabolic Stress. Cell Metabolism 30, 157-173.e157, 2019.
29
Zhao, J., Lee, E. E., Kim, J., Yang, R., Chamseddin, B., Ni, C., Gusho, E., Xie, Y.,
Chiang, C. M., Buszczak, M., Zhan, X., Laimins, L. & Wang, R. C. Transforming
activity of an oncoprotein-encoding circular RNA from human papillomavirus. Nature
Communications 10, 2300, 2019.
30
Ouyang, H., Mou, L., Luk, C., Liu, N., Karaskova, J., Squire, J. & Tsao, M. S.
Immortal human pancreatic duct epithelial cell lines with near normal genotype and
phenotype. The American Journal of Pathology 157, 1623-1631, 2000.
31
Lee, K. M., Yasuda, H., Hollingsworth, M. A. & Ouellette, M. M. Notch 2-positive
progenitors with the intrinsic ability to give rise to pancreatic ductal cells. Laboratory
Investigation; A Journal of Technical Methods and Pathology 85, 1003-1012, 2005.
32
Chen, Y., Chen, Y., Shi, C., Huang, Z., Zhang, Y., Li, S., Li, Y., Ye, J., Yu, C., Li, Z.,
- 63 -
Zhang, X., Wang, J., Yang, H., Fang, L. & Chen, Q. SOAPnuke: a MapReduce
acceleration-supported software for integrated quality control and preprocessing of
high-throughput sequencing data. GigaScience 7, 1-6, 2018.
33
Gao, Y., Wang, J. & Zhao, F. CIRI: an efficient and unbiased algorithm for de novo
circular RNA identification. Genome Biology 16, 4, 2015.
34
Gao, Y., Zhang, J. & Zhao, F. Circular RNA identification based on multiple seed
matching. Briefings in Bioinformatics 19, 803-810, 2018.
35
Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and
dispersion for RNA-seq data with DESeq2. Genome Biology 15, 550-550, 2014.
36
Kramer, M. C., Liang, D., Tatomer, D. C., Gold, B., March, Z. M., Cherry, S. &
Wilusz, J. E. Combinatorial control of Drosophila circular RNA expression by intronic
repeats, hnRNPs, and SR proteins. Genes & Development 29, 2168-2182, 2015.
37
Ono, Y., Sugitani, A., Karasaki, H., Ogata, M., Nozaki, R., Sasajima, J., Yokochi, T.,
Asahara, S., Koizumi, K., Ando, K., Hironaka, K., Daito, T. & Mizukami, Y. An
improved digital polymerase chain reaction protocol to capture low-copy KRAS
mutations in plasma cell-free DNA by resolving 'subsampling' issues. Molecular
Oncology 11, 1448-1458, 2017.
38
Bernard, V., Kim, D. U., San Lucas, F. A., Castillo, J., Allenson, K., Mulu, F. C.,
Stephens, B. M., Huang, J., Semaan, A., Guerrero, P. A., Kamyabi, N., Zhao, J., Hurd,
- 64 -
M. W., Koay, E. J., Taniguchi, C. M., Herman, J. M., Javle, M., Wolff, R., Katz, M.,
Varadhachary, G., Maitra, A. & Alvarez, H. A. Circulating Nucleic Acids Are
Associated With Outcomes of Patients With Pancreatic Cancer. Gastroenterology 156,
108-118.e104, 2019.
39
Dudekula, D. B., Panda, A. C., Grammatikakis, I., De, S., Abdelmohsen, K. &
Gorospe, M. CircInteractome: A web tool for exploring circular RNAs and their
interacting proteins and microRNAs. RNA Biology 13, 34-42, 2016.
40
Fan, C., Lei, X., Fang, Z., Jiang, Q. & Wu, F. X. CircR2Disease: a manually curated
database for experimentally supported circular RNAs associated with various diseases.
Database : The Journal of Biological Databases and Curation 2018, 2018.
41
Meng, X., Hu, D., Zhang, P., Chen, Q. & Chen, M. CircFunBase: a database for
functional circular RNAs. Database : The Journal of Biological Databases and
Curation 2019, 2019.
42
Liu, W. & Wang, X. Prediction of functional microRNA targets by integrative
modeling of microRNA binding and target expression data. Genome Biology 20, 18,
2019.
43
Yang, F., Liu, D. Y., Guo, J. T., Ge, N., Zhu, P., Liu, X., Wang, S., Wang, G. X. & Sun,
S. Y. Circular RNA circ-LDLRAD3 as a biomarker in diagnosis of pancreatic cancer.
World Journal of Gastroenterology 23, 8345-8354, 2017.
- 65 -
44
Li, Q., Geng, S., Yuan, H., Li, Y., Zhang, S., Pu, L., Ge, J., Niu, X., Li, Y. & Jiang, H.
Circular RNA expression profiles in extracellular vesicles from the plasma of patients
with pancreatic ductal adenocarcinoma. FEBS Open Bio 9, 2052-2062, 2019.
45
Li, J., Li, Z., Jiang, P., Peng, M., Zhang, X., Chen, K., Liu, H., Bi, H., Liu, X. & Li, X.
Circular RNA IARS (circ-IARS) secreted by pancreatic cancer cells and located
within exosomes regulates endothelial monolayer permeability to promote tumor
metastasis. Journal of Experimental & Clinical Cancer Research : CR 37, 177, 2018.
46
Li, Z., Yanfang, W., Li, J., Jiang, P., Peng, T., Chen, K., Zhao, X., Zhang, Y., Zhen, P.,
Zhu, J. & Li, X. Tumor-released exosomal circular RNA PDE8A promotes invasive
growth via the miR-338/MACC1/MET pathway in pancreatic cancer. Cancer Letters
432, 237-250, 2018.
47
Zhang, X. O., Wang, H. B., Zhang, Y., Lu, X., Chen, L. L. & Yang, L. Complementary
sequence-mediated exon circularization. Cell 159, 134-147, 2014.
48
Limb, C., Liu, D. S. K., Veno, M. T., Rees, E., Krell, J., Bagwan, I. N., Giovannetti, E.,
Pandha, H., Strobel, O., Rockall, T. A. & Frampton, A. E. The Role of Circular RNAs
in Pancreatic Ductal Adenocarcinoma and Biliary-Tract Cancers. Cancers 12, 2020.
49
Tempero, M. A., Uchida, E., Takasaki, H., Burnett, D. A., Steplewski, Z. & Pour, P. M.
Relationship of carbohydrate antigen 19-9 and Lewis antigens in pancreatic cancer.
Cancer Research 47, 5501-5503, 1987.
- 66 -
50
Guo, M., Luo, G., Lu, R., Shi, W., Cheng, H., Lu, Y., Jin, K., Yang, C., Wang, Z., Long,
J., Xu, J., Ni, Q., Liu, C. & Yu, X. Distribution of Lewis and Secretor polymorphisms
and corresponding CA19-9 antigen expression in a Chinese population. FEBS Open
Bio 7, 1660-1671, 2017.
51
Hori, M., Matsuda, T., Shibata, A., Katanoda, K., Sobue, T. & Nishimoto, H. Cancer
incidence and incidence rates in Japan in 2009: a study of 32 population-based cancer
registries for the Monitoring of Cancer Incidence in Japan (MCIJ) project. Japanese
Journal of Clinical Oncology 45, 884-891, 2015.
52
Oyama, H., Tada, M., Takagi, K., Tateishi, K., Hamada, T., Nakai, Y., Hakuta, R.,
Ijichi, H., Ishigaki, K., Kanai, S., Kogure, H., Mizuno, S., Saito, K., Saito, T., Sato, T.,
Suzuki, T., Takahara, N., Morishita, Y., Arita, J., Hasegawa, K., Tanaka, M., Fukayama,
M. & Koike, K. Long-term Risk of Malignancy in Branch-Duct Intraductal Papillary
Mucinous Neoplasms. Gastroenterology 158, 226-237.e225, 2020.
- 67 -
8.謝辞
本論文の作成にあたり懇切なる御指導ならびに御鞭撻を賜りました東京大学医学部消化器
内科 小池和彦教授に謹んで御礼申し上げます。
本研究の遂行にあたりまして以下の先生方に多大なる御協力を賜りましたことをここに記し、
深く感謝申し上げます。
東京大学消化器内科
大塚基之先生、岩田琢磨先生、田中恵理先生、關場一磨先生、柴田智華子先生
大宮シティクリニック
森山優先生、中川良先生
がん研究所、がんエピゲノムプロジェクト
丸山玲緒先生
その他、様々な点で御協力いただいた東京大学消化器内科の先生方に感謝いたします。
- 68 -
...