Functional analysis and therapeutic application of clusterin, a candidate gene involved in resistance to anticancer agents in cholangiocarcinoma
Project/Area Number |
20K07394
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 49020:Human pathology-related
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Research Institution | Oita University |
Principal Investigator |
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Co-Investigator(Kenkyū-buntansha) |
守山 正胤 大分大学, 医学部, 客員研究員 (90239707)
泥谷 直樹 大分大学, 医学部, 准教授 (80305036)
兒玉 雅明 大分大学, 福祉健康科学部, 教授 (20332893)
沖本 忠義 大分大学, 医学部, 准教授 (90381037)
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Project Period (FY) |
2020-04-01 – 2023-03-31
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Project Status |
Completed (Fiscal Year 2022)
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Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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Keywords | 抗癌剤抵抗性 / 胆管癌 / 胆汁 / オルガノイド / clusterin / 抗がん剤抵抗性 |
Outline of Research at the Start |
胆管癌は予後不良な癌腫のひとつで5年生存率は20%程度に留まる。その理由のひとつとして、切除不可能な症例や術後再発症例に対する有効な化学療法がないことが挙げられる。現在、胆管癌に対してGEMとCDDP が単独または併用投与されるが、生存期間はわずかに延長するものの ほぼ全症例が癌死に至る。 胆管癌の予後を改善するためには、治療抵抗性に関わる分子メカニズムを解明し、その知見に基づく新規治療法の開発が必要である。 本研究では、ヒト胆管癌のGEM/CDDP治療抵抗性に関わる候補分子としてCLU(Clusterin;糖タンパク質の一種)に注目し、その発現状況、機能的意義、治療応用性について検証する。
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Outline of Final Research Achievements |
Patient-derived tumor organoids have considerable potential as an in vitro diagnostic tool for drug susceptibility testing. We investigated whether bile collected for diagnostic purposes could be a potential source for the establishment of biliary cancer organoids. Among 68 cases of biliary cancer, we successfully generated 60 bile-derived organoids (BDOs) from individual patients. They also harbored mutations in KRAS and TP53 at frequencies of 15% and 55%, respectively. To enrich the cancer organoids by removing contaminated noncancerous components of BDOs, we attempted to verify the effectiveness of 3 different procedures, including repeat passage, xenografting, and selection with an MDM2 inhibitor for TP53 mutation-harboring BDOs. By monitoring the sequence and expression of mutated TP53, we found that all these procedures successfully enriched the cancer organoids.
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Academic Significance and Societal Importance of the Research Achievements |
診断目的で採取した胆汁を用いて胆管癌オルガノイドを樹立する方法は、従来の生検組織や手術検体から樹立する方法に比べて、非侵襲的であり、手術不能な進行癌症例にも適用される。また、同一患者から経時的に癌オルガノイドを樹立することができるため、癌の進展に伴う悪性形質の変化やその原因となるドライバー遺伝子の検索に有用である。今後、抗癌剤や分子標的治療薬の感受性を予測するための体外診断ツールとして臨床応用され、胆管癌患者の治療成績の改善に寄与することを期待する。
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Report
(4 results)
Research Products
(27 results)
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[Journal Article] Efficient Establishment of Bile-Derived Organoids From Patients With Biliary Cancer.2023
Author(s)
Kinoshita K, Tsukamoto Y, Hirashita Y, Fuchino T, Kurogi S, Uchida T, Nakada C, Matsumoto T, Okamoto K, Motomura M, Fukuchi S, Sagami R, Nagai T, Gotoh Y, Fukuda K, Ogawa R, Mizukami K, Okimoto T, Kodama M, Murakami K, Moriyama M, Hijiya N.
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Journal Title
Lab Invest.
Volume: 103
Issue: 6
Pages: 100105-100105
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Involvement of clusterin expression in the refractory response of pancreatic cancer cells to a MEK inhibitor.2023
Author(s)
Amada K, Hijiya N, Ikarimoto S, Yanagihara K, Hanada T, Hidano S, Kurogi S, Tsukamoto Y, Nakada C, Kinoshita K, Hirashita Y, Uchida T, Shin T, Yada K, Hirashita T, Kobayashi T, Murakami K, Inomata M, Shirao K, Aoki M, Takekawa M, Moriyama M.
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Journal Title
Cancer Sci.
Volume: 114
Issue: 5
Pages: 2189-2202
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Kyoto international consensus report on anatomy, pathophysiology and clinical significance of the gastro-oesophageal junction2022
Author(s)
Sugano K, Stuart J Spechler, Emad M El-Omar, Kenneth E L McColl,Takubo K, Gotoda T, Fujishiro M, Iijima K, Inoue H, Kawai T, Kinoshita Y, Miwa H, Mukaisho K, Murakami K, Seto Y, Tajiri H, Bhatia S,Myung-Gyu Choi, Rebecca C Fitzgerald,Kwong Ming Fock, Khean-Lee Goh, Peter Malfertheiner etc.
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Journal Title
Gut
Volume: 71(8)
Pages: 1488-1514
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Enhanced phosphorylation of c-Jun by cisplatin treatment as a potential predictive biomarker for cisplatin response in combination with patient-derived tumor organoids.2022
Author(s)
Tsukamoto Y, Kurogi S, Shibata T, Suzuki K, Hirashita Y, Fumoto S, Yano S, Yanagihara K, Nakada C, Mieno F, Kinoshita K, Fuchino T, Mizukami K, Ueda Y, Etoh T, Uchida T, Hanada T, Takekawa M, Daa T, Shirao K, Hironaka S, Murakami K, Inomata M, Hijiya N, Moriyama M.
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Journal Title
Lab Invest.
Volume: 102 (12)
Issue: 12
Pages: 1355-1366
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Downregulation of ZNF395 Drives Progression of Pancreatic Ductal Adenocarcinoma through Enhancement of Growth Potential.2021
Author(s)
Kurogi S, Hijiya N, Hidano S, Sato S, Uchida T, Tsukamoto Y, Nakada C, Yada K, Hirashita T, Inomata M, Murakami K, Takahashi N, Kobayashi T, Moriyama M.
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Journal Title
Pathobiology
Volume: 2021
Issue: 5
Pages: 1-9
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Development of Pancreatic Acinar Cell Metaplasia During Gastric Repair in a Rat Duodenal Contents Reflux Model.2020
Author(s)
Wada Y, Mukaisho KI, Kanai S, Nakayama T, Fukuda M, Mizukami K, Okimoto T, Kodama M, Sugihara H, Murakami K, Kushima R.
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Journal Title
Dig Dis Sci.
Volume: 66
Issue: 4
Pages: 1072-1079
DOI
NAID
Related Report
Peer Reviewed / Open Access
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[Journal Article] Helicobacter pylori infection modulates endogenous hydrogen sulfide production in gastric cancer AGS cells2020
Author(s)
Kawahara Y, Hirashita Y, Tamura C, Kudo Y, Sakai K, Togo K, Fukuda K, Matsunari O, Okamoto K, Ogawa R, Mizukami K, Okimoto T, Kodama M, Murakami K
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Journal Title
Helicobacter
Volume: 25
Issue: 5
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] A transgenic mouse expressing miR-210 in proximal tubule cells shows mitochondrial alteration: possible association of miR-210 with a shift in energy metabolism.2020
Author(s)
Nakada C, Hijiya N, Tsukamoto Y, Yano S, Kai T, Uchida T, Kimoto M, Takahashi M, Daa T, Matsuura K, Shin T, Mimata H, Moriyama M.
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Journal Title
J Pathol.
Volume: in press
Issue: 1
Pages: 12-25
DOI
Related Report
Peer Reviewed
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