Signal Activation of Hepatitis B Virus–Related Hepatocarcinogenesis by Up-regulation of SUV39h1
概要
ָ Ғ ช સ ช གྷ ༁
Signal Activation of Hepatitis B Virus–Related
Hepatocarcinogenesis
by
Up-regulation
of
SUV39h1
㸦SUV39h1 Ⓨ⌧ஹ㐍ࡼࡿ B ᆺ⫢⅖࢘ࣝࢫ㛵㐃⫢
Ⓨ⒴ࡢಙྕάᛶ㸧
The Journal of Infectious Diseases, 222(12):
2061–2070, 2020.
➉ෆ ὈỤ
㸦་ṑ⸆ಖᏛ◊✲⛉ ་ṑ⸆Ꮫᑓᨷ㸧
㸯㸧⫼ᬒ㸬┠ⓗ
B ᆺ⫢⅖࢘ࣝࢫ(HBV)ឤᰁᝈ⪅࠾࠸࡚ࡣ㸪ᢠ࢘ࣝࢫ⒪ἲࡼࡿ HBV ቑṪࡢไᚚࡣྍ⬟࡛
࠶ࡿࡀ㸪⫢Ⓨ⒴ࡀၥ㢟࡛࠶ࡿ㸬HBV 㛵㐃⺮ⓑࡢ 1 ࡘ࡛࠶ࡿ HBx ⺮ⓑࡣᝏᛶࡢㄏᑟࡸ࣑ࢺࢥ
ࣥࢻࣜᶵ⬟࡞ࢆࡋ㸪⫢Ⓨ⒴㛵ࡋ࡚࠸ࡿ⪃࠼ࡽࢀ࡚࠸ࡿ㸬୍᪉㸪SUV39h1 ࡀࣄ
ࢫࢺࣥࡢ࣓ࢳࣝ㓝⣲ࡋ࡚Ⓨぢࡉࢀ࡚௨㝆㸪ᵝࠎ࡞ࣄࢫࢺ࣓ࣥࢳࣝ㓝⣲ࡀྠᐃࡉࢀࠊྛ㓝⣲
ࡀ≉ᐃࡢࣄࢫࢺࣥ࠶ࡿࣜࢪࣥṧᇶࢆ࣓ࢳࣝࡋ㸪ࢡ࣐ࣟࢳࣥᵓ㐀ࡀኚࡉࡏ㸪㑇ఏᏊࡢ㌿ࢆ
ไᚚࡋ࡚࠸ࡿࡇࡀ᫂ࡽ࡞ࡗ࡚࠸ࡿࡀ㸪HBx SUV39h1 ࡢ┦స⏝㛵ࡋ࡚ࡣ᫂࡞Ⅼ
ࡀከ࠸㸬ᮏ◊✲࡛ࡣ㸪ࣄࢺ⫢⣽⬊⛣᳜࣐࢘ࢫ㸦uPA-SCID ࣐࢘ࢫ㸧ࢆ⏝࠸࡚ HBV ᣢ⥆ឤᰁ
క࠸㸪⫢⤌⧊ࡢ⥙⨶ⓗ࡞㑇ఏᏊⓎ⌧ゎᯒࡽᢳฟࡉࢀࡓ SUV39h1 㑇ఏᏊ╔┠ࡋ㸪HBV ឤ
ᰁ SUV39h1 ࡢ┦స⏝ࢆゎᯒࡋ㸪⫢Ⓨ⒴࣓࢝ࢽࢬ࣒ࡢᙳ㡪ࡸ HBV ቑṪࡢᙳ㡪ࡘ࠸
᳨࡚ウࡋࡓ㸬
㸰㸧᪉ἲ࠾ࡼࡧ⤖ᯝ
ྛ࣐࢘ࢫ 106 copy ࡢ HBV(genotype C)ࢆྵࡴࣄࢺ⾑Ύࢆ࣐࢘ࢫᑿ㟼⬦⤒⏤࡛᥋✀ᚋ㸪⤒ⓗ
HBV DNA ࢆ real time PCR ࡛ ᐃࡋࡓࡇࢁឤᰁ᪩ᮇ(ឤᰁ 3 ᪥┠)ࢆ㝖ࡁࡍ࡚ࡢ⩌࡛ᐃ
㔞ྍ⬟࡛࠶ࡗࡓ㸬
ࡇࢀࡲ࡛⾜ࡗࡓ cDNA ࣐ࢡࣟࣞࡸḟୡ௦ࢩ࣮ࢡ࢚ࣥࢫࡼࡿ᳨ウ࡛ࡣ㸪
HBV ࡢ▷ᮇឤᰁ࡛ࡣ⫢⣽⬊ෆ࠾ࡅࡿ SUV39h1 ࡢⓎ⌧ୖ᪼ࡣㄆࡵ࡞ࡽࢀ࡞ࡗࡓ㸬ᮏ◊✲࡛
ࡣࡉࡽ㛗ᮇࡢほᐹࡢࡓࡵឤᰁ 238 ᪥ࡲ࡛ࡢ࣐࢘ࢫ⫢⣽⬊ෆࡢ SUV39h1 Ⓨ⌧ࢆ real time PCR
ḟୡ௦ࢩ࣮ࢡ࢚ࣥࢫࢆ⏝࠸࡚ᐃ㔞ࡋࡓ㸬ࣄࢺ⫢⣽⬊࠾ࡅࡿ SUV39h1 Ⓨ⌧ࡣ HBV ឤᰁ 56
᪥ᚋࡲ࡛ኚࡋ࡞ࡗࡓࡀ㸪ឤᰁ 238 ᪥ᚋࡢ࣐࢘ࢫ࡛ࡣ HBV 㠀ឤᰁࡲࡓࡣ▷ᮇឤᰁ࣐࢘ࢫẚ
㍑ࡋ࡚ SUV39h1 ࡢ᭷ព࡞Ⓨ⌧ୖ᪼ࢆㄆࡵࡓ㸬
ձ
⫢⒴ᝈ⪅࡛ࡣ㸪⒴⤌⧊ࡢ SUV39h1 Ⓨ⌧ࡀ㧗ࡃ㸪ࣄࢫࢺࣥ H3-K9 ࢺ࣓ࣜࢳࣝࡀஹ㐍ࡋࡓ
࡛ࡣ↓Ⓨ⏕Ꮡ⋡ࡀ᭷ពప࠸ሗ࿌ࡉࢀ࡚࠸ࡿ㸬ࡑࡇ࡛ 5 ࡢ⫢⒴ᡭ⾡ࡢ⫢⤌
⧊ࢆ⏝࠸࡚ SUV39h1 ࡢ㑇ఏᏊⓎ⌧ࢆᐃ㔞ࡋࡓࡇࢁ㸪⒴㒊࡛ࡢⓎ⌧㔞ࡣ㠀⒴㒊ẚ㍑ࡋ
࡚⣙ 2.1 ಸஹ㐍ࡋ࡚࠾ࡾ㸪SUV39h1 ࡢ⣽⬊ෆⓎ⌧ࡢஹ㐍ࡀ⒴㛵㐃ࡋ࡚࠸ࡿࡇࡀ♧၀
ࡉࢀࡓ㸬
ղ
SUV39h1 ࡢ⒴㒊࠾ࡅࡿⓎ⌧ஹ㐍ࡀ☜ㄆࡉࢀࡓࡇࡽ㸪 HBV 㛵㐃⫢⒴࠾ࡅࡿ
SUV39h1 ࡢᙳ㡪ࡘ࠸᳨࡚ウࡋࡓ㸬HBV 㛵㐃⫢⒴࡛ࡣ HBV ࢤࣀ࣒ࡼࡾ⏘⏕ࡉࢀࡿ HBx
⺮ⓑࡀ⫢Ⓨ⒴㛵ࡍࡿࡇࡀሗ࿌ࡉࢀ࡚࠾ࡾ㸪HBx SUV39h1 ࡢ┦స⏝ࢆゎᯒࡋࡓ㸬
HBx ࠾ࡼࡧ SUV39h1 Ⓨ⌧ࣉࣛࢫ࣑ࢻࢆస〇ࡋ㸪HepG2 ⣽⬊ transfection ࡋࡓᚋ㸪⣽⬊
ෆ࠾ࡅࡿ୧⺮ⓑࡢ interaction ࢆゎᯒࡋࡓ㸬චỿ㝆ࡢ⤖ᯝ㸪୧⺮ⓑࡀ interaction ࡍࡿ
ࡇࡀ☜ㄆࡉࢀࡓ㸬᭦㸪୧⺮ⓑ㛫ࡀ interaction ࡍࡿ㡿ᇦࡢྠᐃࡢࡓࡵ㸪HBx ࠾ࡼࡧ
SUV39h1 ࡢ㛗ࡶࡋࡃࡣ㒊ศ㛗ࢆ⤌ࡳ㎸ࢇࡔࣉࣛࢫ࣑ࢻࢆస〇ࡋ㸪ྠᵝࡢ᳨ウࢆ⾜ࡗࡓ
ࡇࢁ㸪HBx ࡣ SUV39h1 ࡢ 89㹼233 ␒┠ࡢ㡿ᇦ㸦SET domain 㡿ᇦ㸧
㸪SUV39h1 ࡣ㸪HBx
ࡢ 52㹼102 ␒┠ࡢ㡿ᇦ㸦co-activator domain 㡿ᇦ㸧 interaction ࡍࡿࡇࡀ᫂ࡽ࡞
ࡗࡓ㸬
ճ
⥆࠸࡚㸪HBx SUV39h1 ඹⓎ⌧ࡼࡿⓎ⒴࣓࢝ࢽࢬ࣒ࡢᙳ㡪ࡘ࠸᳨࡚ウࡋࡓ㸬ࡇࢀ
ࡲ࡛ HBx ࡼࡾⓎ⌧ࡀஹ㐍ࡋ⫢Ⓨ⒴ᐤࡍࡿࡇࡀሗ࿌ࡉࢀ࡚࠸ࡿ ATF6㸪AFP㸪
GADD45a㸪DUSP1 ࡢ 4 㑇ఏᏊ╔┠ࡋゎᯒࢆ⾜ࡗࡓ㸬SUV39h1 ࠾ࡼࡧ HBV ࢆ HepG2
⣽⬊ transfection ᚋ㸪⣽⬊ෆࡢ mRNA Ⓨ⌧ኚࢆ☜ㄆࡋࡓࡇࢁ㸪HBV SUV39h1
ࡢ୧⺮ⓑࡢᏑᅾୗ࡛㸪ࡇࢀࡽ 4 㑇ఏᏊࡢ᭷ព࡞Ⓨ⌧ஹ㐍ࢆㄆࡵࡓ㸬᭦㸪HBV 㛵㐃⺮ⓑⓎ
⌧ࣉࣛࢫ࣑ࢻࢆ⏝࠸࡚ྠᵝࡢ᳨ウࢆ⾜ࡗࡓࡇࢁ㸪4 㑇ఏᏊࡣ HBx Ⓨ⌧ࡢࡳⓎ⌧ஹ㐍ࢆ
ㄆࡵ㸪ࡉࡽ SUV39h1 ࢆඹⓎ⌧ࡍࡿࡇࡼࡾࡑࡢⓎ⌧㔞ࡢቑᙉࢆㄆࡵࡓ㸬
մ
୍᪉㸪HBx ࡀ SUV39h1 ࡢ࣓ࢳࣝࢺࣛࣥࢫࣇ࢙࣮ࣛࢮάᛶࢆቑᙉࡍࡿྍ⬟ᛶࢆ⪃៖ࡋ㸪HBx
࠾ࡼࡧ SUV39h1 ࡢ recombinant protein ࢆస〇ᚋ㸪HBx ࡢ᭷↓ࡼࡿ Histone H3 ࣓ࢳ
ࣝࡢ⛬ᗘࡢኚࢆ in vitro methyltransferase assay ᳨࡚ウࡋࡓ㸬 SUV39h1 Ꮡᅾୗ࡛
Histone H3 ࡢ࣓ࢳࣝࡀほᐹࡉࢀ㸪 SUV39h1 HBx ࡢඹᏑᅾୗ࡛ࡑࡢ࣓ࢳࣝࡀቑᙉ
ࡉࢀࡿࡇࡀ☜ㄆࡉࢀࡓ㸬௨ୖࡽ㸪HBx ࡢ SUV39h1 ࡼࡿ Histon H3 ࡢ࣓ࢳࣝࢆಁ
㐍ࡍࡿྍ⬟ᛶࡀ♧၀ࡉࢀࡓ㸬
㸱㸧⪃ᐹ
SUV39h1 HBx ࡢ┦స⏝ࡀ࠸άᛶࢆ㧗ࡵ㸪HBx ࢆࡋࡓ⫢Ⓨ⒴ࢆㄏᑟࡋ࡚࠸ࡿࡇࡀ
♧၀ࡉࢀࡓ㸬SUV39h1 ࡢ HBx ᶵ⬟άᛶࡢ࣓࢝ࢽࢬ࣒ࢆゎᯒࡍࡿࡇࡼࡾ㸪HBV 㛵㐃Ⓨ⒴
࣓࢝ࢽࢬ࣒ࡢゎ᫂࡞ࡽࡧ᪂ࡓ࡞⫢⒴⒪ᶆⓗ࡞ࡿྍ⬟ᛶࡀ♧၀ࡉࢀࡓ㸬