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Expression of Fhit, Mlh1, and P53 protein in human gallbladder carcinoma

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ࡇ࠺ࡔ ࡲࡉࡣࡿ 

Ꮫ ఩ ࡢ ✀ 㢮

༤ኈ㸦་Ꮫ㸧

Ꮫ ఩ グ ␒ ྕ

⏥➨㸲㸴㸰ྕ

Ꮫ ఩ ᤵ ୚ ᖺ ᭶ ᪥

ᖹᡂ㸯㸴ᖺ 㸱᭶㸯㸴᪥

Ꮫ ఩ ᤵ ୚ ࡢ せ ௳

Ꮫ఩つ๎➨㸲᮲➨㸯㡯ヱᙜ

Ꮫ ఩ ㄽ ᩥ 㢟 ┠

Expression of Fhit, Mlh1, and P53 protein in human

gallbladder carcinoma

㸦⫹ᄞ⒴࡟࠾ࡅࡿ FhitࠊMlh1 ཬࡧ P53 ⺮ⓑⓎ⌧࡟㛵ࡍ

ࡿ᳨ウ㸧

Ꮫ఩ㄽᩥᑂᰝጤဨ

୺ᰝ ㈅ ཎ ಙ ᫂



๪ᰝ ஭ ⸨ ஂ 㞝  ᮧ ⬥ ⩏ ࿴ 



Ꮫ ఩ ㄽ ᩥ ࡢ ෆ ᐜ ࡢ せ ᪨

 ⫹ᄞ⒴ࡣ᪩ᮇデ᩿ࡀ㞴ࡋࡃࠊࡑࡢணᚋࡣ୙Ⰻ࡛࠶ࡿࠋ⫹ᄞ⒴ࡢ๓㥑⑓ኚ࡜ࡋ࡚⫹ᄞ⭢⭘ࡀ࠶ࡆࡽࢀ

࡚࠸ࡿࡀࠊ⫹ᄞ⒴ࡢⓎ⒴࣓࢝ࢽࢬ࣒ࡣ༑ศ࡟ゎ᫂ࡉࢀ࡚࠸࡞࠸ࠋFragile Histidine Triad (FHIT)㑇ఏ

Ꮚࡣ 3p14.2 ࡟఩⨨ࡋྛ✀ࡢ⒴࡛␗ᖖࡀㄆࡵࡽࢀࠊ⒴ᢚไ㑇ఏᏊࡢ୍ࡘ࡜ࡋ࡚ὀ┠ࡉࢀ࡚࠸ࡿࠋࡑࡢ 㑇ఏᏊ⏘≀࡛࠶ࡿ Fhit ⺮ⓑⓎ⌧ࡢపୗࡣ DNAࠊRNA ࣞ࣋ࣝࡢ␗ᖖࢆ཯ᫎࡋ࡚࠸ࡿ࡜⪃࠼ࡽࢀ࡚࠸ ࡿࠋࡲࡓࠊྛ✀⒴࡟࠾࠸࡚ DNA ࣑ࢫ࣐ࢵࢳಟ᚟㑇ఏᏊ࡛࠶ࡿMLH1㑇ఏᏊࡢࣉ࣮ࣟࣔࢱ࣮㡿ᇦࡢ࣓ ࢳࣝ໬ࡀㄆࡵࡽࢀࠊࡑࡢ⤖ᯝ࡜ࡋ࡚ Mlh1 ⺮ⓑⓎ⌧ࡢᾘኻࠊపୗࡀሗ࿌ࡉࢀ࡚࠸ࡿࠋࡉࡽ࡟᭱㏆ࡢሗ ࿌࡟࠾࠸࡚ DNA ࣑ࢫ࣐ࢵࢳಟ᚟㑇ఏᏊ␗ᖖࡀFHIT㑇ఏᏊ␗ᖖࢆᘬࡁ㉳ࡇࡍྍ⬟ᛶࡀ♧ࡉࢀ࡚࠸ࡿࠋ ௒ᅇᡃࠎࡣ⒴ᢚไ㑇ఏᏊࡢ୍ࡘ࡛࠶ࡿFHIT 㑇ఏᏊ࡜࣑ࢫ࣐ࢵࢳಟ᚟㑇ఏᏊ࡛࠶ࡿMLH1㑇ఏᏊ࡟ ὀ┠ࡋࠊࡑࢀࡒࢀࡢ⺮ⓑⓎ⌧࠿ࡽࠊ⫹ᄞ⒴࡟࠾ࡅࡿFHIT 㑇ఏᏊ␗ᖖ࡜MLH1 㑇ఏᏊ␗ᖖ࡜ࡢ㛵ಀ ࡢ᭷↓ࢆホ౯ࡋࡓࠋࡲࡓ P53 ⺮ⓑⓎ⌧ࡶྵࡵ࡚ࠊࡇࢀࡽ 3 ࡘࡢ⺮ⓑⓎ⌧࡜⮫ᗋ⑓⌮Ꮫⓗᡤぢࢆẚ㍑᳨ ウࡋࡓࠋ ᪉ ἲ  1991 ᖺ࠿ࡽ 2001 ᖺ࡟࠿ࡅ࡚እ⛉ⓗ࡟ษ㝖ࡉࢀࡓ⫹ᄞ⒴ 20 ౛㸦㧗ศ໬ᆺ 7 ౛ࠊ୰ศ໬ᆺ 5 ౛ࠊங 㢌ᆺ 6 ౛ࠊపศ໬ᆺ 2 ౛㸧࡜⫹ᄞ⭢⭘ 3 ౛ࡢ࣐࣍ࣝࣜࣥᅛᐃࣃࣛࣇ࢕ࣥໟᇙᮦᩱࢆ⏝࠸࡚ࠊᢠ FHIT ࢘ࢧࢠ࣏ࣜࢡ࣮ࣟࢼࣝᢠయࠊᢠ MLH1 ࣐࢘ࢫࣔࣀࢡ࣮ࣟࢼࣝᢠయཬࡧᢠ P53 ࣐࢘ࢫࣔࣀࢡ࣮ࣟࢼࣝ ᢠయࢆ⏝࠸ࠊABC ἲ࡟ࡼࡾච␿⤌⧊໬ᏛᰁⰍࢆ⾜ࡗࡓࠋFhit ච␿⤌⧊໬ᏛᰁⰍࡢホ౯ࡣࠊᰁⰍ㡿ᇦ ࡜ᰁⰍᙉᗘ࡛⾜࠸ࠊⓎ⌧㡿ᇦ࡛ࡣࠊ0; <5%ࠊ 1; 5㹼25%ࠊ 2; 25㹼50%ࠊ 3; 50㹼75%ࠊ 4; >75%࡜ࠊ Ⓨ⌧ᙉᗘ࡛ࡣࠊ0; 㝜ᛶࠊ 1+; ᚤᙅࠊ 2+; ୰➼ᗘࠊ 3+; ṇᖖ࡜ྠ➼࡜Ⅼᩘ໬ࡋࠊ୧⪅ࢆ᥃ࡅྜࢃࡏ ᭱⤊ⓗࢫࢥ࢔࡜ࡋࡓ㸦⠊ᅖ 0㹼12㸧ࠋࢫࢥ࢔ 0㹼4 ࢆⴭ᫂ῶᙅࡲࡓࡣᾘኻࠊ5㹼8 ࢆ୰㛫Ⓨ⌧ࠊ9㹼12 ࢆ 㧗ᗘⓎ⌧࡜ࡋࡓࠋMlh1 ච␿ᰁⰍ࡛ࡣࠊ⭘⒆⣽⬊ࡢ᰾࡛ࡢⓎ⌧ࡀ 30%௨ୗࢆ㝜ᛶ࡜ホ౯ࡋࡓࠋP53 ච ␿ᰁⰍ࡛ࡣࠊ⭘⒆⣽⬊ࡢ 25%௨ୖࡢ᰾࡛ࡢⓎ⌧ࢆ㝧ᛶ࡜ホ౯ࡋࡓࠋ

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⤖ ᯝ  Fhit ⺮ⓑࡣࠊṇᖖ⫹ᄞୖ⓶⣽⬊࡛ࡣ⣽⬊㉁࡟ᙉࡃᰁⰍࡉࢀࡓࠋFhit ⺮ⓑⓎ⌧ࡢῶᙅࡲࡓࡣᾘኻࡣࠊ ⫹ᄞ⒴ 20 ౛୰ 9 ౛(45%)࡛ㄆࡵࡽࢀࠊࡑࡢศ໬ᗘู࡛ࡢෆヂࡣࠊ㧗ศ໬ᆺ⟶≧⭢⒴ࡢ 7 ౛୰ 3 ౛(43%)ࠊ ୰ศ໬ᆺ⟶≧⭢⒴ࡢ 5 ౛୰ 2 ౛(40%)ࠊங㢌ᆺ⭢⒴ࡢ 6 ౛୰ 2 ౛(33%)ࠊపศ໬ᆺ⟶≧⭢⒴ࡢ 2 ౛(100%) ࡛࠶ࡗࡓࠋࡲࡓࠊ⫹ᄞ⭢⭘࡛ࡣ 3 ౛୰ 1 ౛(33%)࡛ Fhit ⺮ⓑⓎ⌧ῶᙅࡀㄆࡵࡽࢀࡓࠋMlh1 ⺮ⓑࡣṇ ᖖ⫹ᄞ࡛ࡣୖ⓶⣽⬊ཬࡧ㛫㉁⣽⬊ࡢ᰾࡟ᰁⰍࡉࢀࡓࠋMlh1 ⺮ⓑⓎ⌧㝜ᛶࡣࠊ⫹ᄞ⒴ 20 ౛୰ 6 ౛(30%)ࠊ ⫹ᄞ⭢⭘ 3 ౛୰ 1 ౛(33%)࡟ㄆࡵࡓࠋFhit ࡜ Mlh1 ⺮ⓑⓎ⌧ࡢ㛵ಀ࡛ࡣࠊFhit ⺮ⓑⓎ⌧ࡀῶᙅࡲࡓࡣ ᾘኻࡋ࡚࠸ࡿ 10 ౛୰ 6 ౛(60%)࡟ Mlh1 㝜ᛶࢆㄆࡵࡓࡀࠊFhit ⺮ⓑⓎ⌧౛㸦୰㛫࠾ࡼࡧ㧗ᗘ㸧࡛ Mlh1 㝜ᛶࡣ 13 ౛୰ 1 ౛(7.7%)ࡢࡳ࡛࠶ࡗࡓ(P=0.0186)ࠋP53 ⺮ⓑࡣࠊ⫹ᄞ⒴ࡢ 55%࡟㐣๫Ⓨ⌧ࡀㄆࡵࡽ ࢀࡓࡀࠊFhit ࡜ P53 ⺮ⓑⓎ⌧࡜ࡢ㛫࡟ࡣ᭷ព࡞㛵㐃ࡣ࡞࠿ࡗࡓࠋࡲࡓࠊFhitࠊMlh1ࠊP53 ⺮ⓑⓎ⌧ ࡜⮫ᗋ⑓⌮Ꮫⓗᡤぢ࡜ࡢ㛵㐃࡟ࡘ࠸࡚ࡶ᳨ウࡋࡓࡀ᭷ព࡞┦㛵ࡣㄆࡵ࡞࠿ࡗࡓࠋ ⪃ ᐹ  ௒ᅇࡢᡃࠎࡢ᳨ウ࡟ࡼࡾࠊ⫹ᄞ⒴ࠊ⫹ᄞ⭢⭘࡛ Fhit ⺮ⓑⓎ⌧ࡢῶᙅࡀ㧗㢖ᗘ࡟ㄆࡵࡽࢀࠊ⫹ᄞ⒴ࡢ Ⓨ⒴࡟㔜せ࡞ᙺ๭ࢆᯝࡓࡋ࡚࠸ࡿ࡜⪃࠼ࡽࢀࡓࠋ୍᪉ࠊ኱⭠⒴࡛ࡣFHIT㑇ఏᏊ␗ᖖ࡜࣑ࢫ࣐ࢵࢳಟ ᚟㑇ఏᏊ␗ᖖࡢ㛵ಀࡀᣦ᦬ࡉࢀ࡚࠸ࡿࡀࠊ⫹ᄞ⒴࡟࠾࠸࡚ࡶ Mlh1 ⺮ⓑⓎ⌧㝜ᛶ౛࡛ Fhit ⺮ⓑⓎ⌧ῶ ᙅࡀ㧗㢖ᗘ࡛࠶ࡾ(P=0.0186)ࠊFHIT㑇ఏᏊࡀ࣑ࢫ࣐ࢵࢳಟ᚟㑇ఏᏊ࡛࠶ࡿMLH1ࡢࢱ࣮ࢤࢵࢺ㑇ఏ Ꮚࡢ୍ࡘ࡛࠶ࡿྍ⬟ᛶࡀ♧၀ࡉࢀࡓࠋ࡞࠾ࠊP53 ⺮ⓑⓎ⌧␗ᖖࡣ⫹ᄞ⭢⭘࡛ࡣㄆࡵࡽࢀࡎࠊ⫹ᄞ⒴ 55% ࡟ㄆࡵࡽࢀࠊp53␗ᖖࡣ⫹ᄞ⒴ࡢ㐍⾜㐣⛬࡟㛵୚ࡍࡿྍ⬟ᛶࡀ⪃࠼ࡽࢀࡓࠋ ⤖ ㄽ  ⫹ᄞ⒴࡟࠾࠸࡚FHIT㑇ఏᏊࡀⓎ⒴࡟ᙉࡃ㛵୚ࡋ࡚࠸ࡿྍ⬟ᛶࡀ♧ࡉࢀࠊࡇࡢ␗ᖖ࡟ࡣࠊ࣑ࢫ࣐ࢵ ࢳಟ᚟㑇ఏᏊ␗ᖖࡢ㛵୚ࡀ᥎ ࡉࢀࡓࠋ

ㄽ ᩥ ᑂ ᰝ ࡢ ⤖ ᯝ ࡢ せ ᪨

 ᮏ◊✲ࡣ⒴ᢚไ㑇ఏᏊ࡛࠶ࡿFHIT㑇ఏᏊ࡜ DNA ࣑ࢫ࣐ࢵࢳಟ᚟㑇ఏᏊ࡛࠶ࡿMLH1㑇ఏᏊ࡟ὀ ┠ࡋࠊච␿⤌⧊໬ᏛᰁⰍ࡟ࡼࡾࠊࡑࢀࡒࢀࡢ㑇ఏᏊ⏘≀ࡢ⺮ⓑⓎ⌧࠿ࡽ⫹ᄞ⒴࡟࠾ࡅࡿFHIT㑇ఏᏊ ␗ᖖ࡜ MLH1 㑇ఏᏊ␗ᖖ࡜ࡢ㛵㐃ࢆ᳨ウࡍࡿ࡜࡜ࡶ࡟ࠊP53 ⺮ⓑⓎ⌧࡟ࡘ࠸࡚ࡶ᳨ウࡋࡓࠋࡑࡢ⤖ ᯝࠊMlh1 ⺮ⓑⓎ⌧㝜ᛶ౛࡛ Fhit ⺮ⓑⓎ⌧ῶᙅࡀ㧗㢖ᗘ࡛࠶ࡾࠊFHIT㑇ఏᏊࡀ࣑ࢫ࣐ࢵࢳಟ᚟㑇ఏ Ꮚ࡛࠶ࡿMLH1㑇ఏᏊࡢࢱ࣮ࢤࢵࢺ㑇ఏᏊࡢ୍ࡘ࡛࠶ࡿྍ⬟ᛶࡀ᫂ࡽ࠿࡟ࡉࢀࡓࠋ࡞࠾ࠊFhit ࡜ P53 ⺮ⓑⓎ⌧࡜ࡢ㛫࡟ࡣ᭷ព࡞┦㛵ࡣ࡞࠿ࡗࡓࠋᮏㄽᩥࡣࠊFHIT 㑇ఏᏊ࡟ὀ┠ࡋࠊ⫹ᄞ⒴࡛ࡢⓎ⒴ᶵᵓ ࡢゎ᫂࡟㈉⊩ࡋࡓࡶࡢ࡛࠶ࡾࠊ᫂ࡽ࠿࡟Ꮫ⾡Ỉ‽ࢆ㧗ࡵࡓࡶࡢ࡜ㄆࡵࡿࠋ

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