Persistent hepatocyte apoptosis promotes tumorigenesis from diethylnitrosamine-transformed hepatocytes through increased oxidative stress, independent of compensatory liver regeneration
Abstract Hepatocellular carcinoma highly occurs in chronic hepatitis livers, where hepatocyte apoptosis is frequently detected. Apoptosis is a mechanism that eliminates mutated cells. Hepatocyte apoptosis induces compensatory liver regeneration, which is believed to contribute to tumor formation. He...
Guardado en:
| Autores principales: | , , , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Nature Portfolio
2021
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/7a3c1eb510344afeaca4f3f59650deab |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:7a3c1eb510344afeaca4f3f59650deab |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:7a3c1eb510344afeaca4f3f59650deab2021-12-02T12:14:50ZPersistent hepatocyte apoptosis promotes tumorigenesis from diethylnitrosamine-transformed hepatocytes through increased oxidative stress, independent of compensatory liver regeneration10.1038/s41598-021-83082-72045-2322https://doaj.org/article/7a3c1eb510344afeaca4f3f59650deab2021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83082-7https://doaj.org/toc/2045-2322Abstract Hepatocellular carcinoma highly occurs in chronic hepatitis livers, where hepatocyte apoptosis is frequently detected. Apoptosis is a mechanism that eliminates mutated cells. Hepatocyte apoptosis induces compensatory liver regeneration, which is believed to contribute to tumor formation. Hepatocyte-specific Mcl-1 knockout mice (Mcl-1Δhep mice) developed persistent hepatocyte apoptosis and compensatory liver regeneration with increased oxidative stress in adulthood but had not yet developed hepatocyte apoptosis at the age of 2 weeks. When diethylnitrosamine (DEN) was administered to 2-week-old Mcl-1Δhep mice, multiple liver tumors were formed at 4 months, while wild-type mice did not develop any tumors. These tumors contained the B-Raf V637E mutation, indicating that DEN-initiated tumorigenesis was promoted by persistent hepatocyte apoptosis. When N-acetyl-L-cysteine was given from 6 weeks of age, DEN-administered Mcl-1Δhep mice had reduced oxidative stress and suppressed tumorigenesis in the liver but showed no changes in hepatocyte apoptosis or proliferation. In conclusion, enhanced tumor formation from DEN-transformed hepatocytes by persistent hepatocyte apoptosis is mediated by increased oxidative stress, independent of compensatory liver regeneration. For patients with livers harboring transformed cells, the control of oxidative stress may suppress hepatocarcinogenesis based on chronic liver injury.Yasutoshi NozakiHayato HikitaSatoshi TanakaKenji FukumotoMakiko UrabeKatsuhiko SatoYuta MyojinAkira DoiKazuhiro MuraiSadatsugu SakaneYoshinobu SaitoTakahiro KodamaRyotaro SakamoriTomohide TatsumiTetsuo TakeharaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-9 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Yasutoshi Nozaki Hayato Hikita Satoshi Tanaka Kenji Fukumoto Makiko Urabe Katsuhiko Sato Yuta Myojin Akira Doi Kazuhiro Murai Sadatsugu Sakane Yoshinobu Saito Takahiro Kodama Ryotaro Sakamori Tomohide Tatsumi Tetsuo Takehara Persistent hepatocyte apoptosis promotes tumorigenesis from diethylnitrosamine-transformed hepatocytes through increased oxidative stress, independent of compensatory liver regeneration |
| description |
Abstract Hepatocellular carcinoma highly occurs in chronic hepatitis livers, where hepatocyte apoptosis is frequently detected. Apoptosis is a mechanism that eliminates mutated cells. Hepatocyte apoptosis induces compensatory liver regeneration, which is believed to contribute to tumor formation. Hepatocyte-specific Mcl-1 knockout mice (Mcl-1Δhep mice) developed persistent hepatocyte apoptosis and compensatory liver regeneration with increased oxidative stress in adulthood but had not yet developed hepatocyte apoptosis at the age of 2 weeks. When diethylnitrosamine (DEN) was administered to 2-week-old Mcl-1Δhep mice, multiple liver tumors were formed at 4 months, while wild-type mice did not develop any tumors. These tumors contained the B-Raf V637E mutation, indicating that DEN-initiated tumorigenesis was promoted by persistent hepatocyte apoptosis. When N-acetyl-L-cysteine was given from 6 weeks of age, DEN-administered Mcl-1Δhep mice had reduced oxidative stress and suppressed tumorigenesis in the liver but showed no changes in hepatocyte apoptosis or proliferation. In conclusion, enhanced tumor formation from DEN-transformed hepatocytes by persistent hepatocyte apoptosis is mediated by increased oxidative stress, independent of compensatory liver regeneration. For patients with livers harboring transformed cells, the control of oxidative stress may suppress hepatocarcinogenesis based on chronic liver injury. |
| format |
article |
| author |
Yasutoshi Nozaki Hayato Hikita Satoshi Tanaka Kenji Fukumoto Makiko Urabe Katsuhiko Sato Yuta Myojin Akira Doi Kazuhiro Murai Sadatsugu Sakane Yoshinobu Saito Takahiro Kodama Ryotaro Sakamori Tomohide Tatsumi Tetsuo Takehara |
| author_facet |
Yasutoshi Nozaki Hayato Hikita Satoshi Tanaka Kenji Fukumoto Makiko Urabe Katsuhiko Sato Yuta Myojin Akira Doi Kazuhiro Murai Sadatsugu Sakane Yoshinobu Saito Takahiro Kodama Ryotaro Sakamori Tomohide Tatsumi Tetsuo Takehara |
| author_sort |
Yasutoshi Nozaki |
| title |
Persistent hepatocyte apoptosis promotes tumorigenesis from diethylnitrosamine-transformed hepatocytes through increased oxidative stress, independent of compensatory liver regeneration |
| title_short |
Persistent hepatocyte apoptosis promotes tumorigenesis from diethylnitrosamine-transformed hepatocytes through increased oxidative stress, independent of compensatory liver regeneration |
| title_full |
Persistent hepatocyte apoptosis promotes tumorigenesis from diethylnitrosamine-transformed hepatocytes through increased oxidative stress, independent of compensatory liver regeneration |
| title_fullStr |
Persistent hepatocyte apoptosis promotes tumorigenesis from diethylnitrosamine-transformed hepatocytes through increased oxidative stress, independent of compensatory liver regeneration |
| title_full_unstemmed |
Persistent hepatocyte apoptosis promotes tumorigenesis from diethylnitrosamine-transformed hepatocytes through increased oxidative stress, independent of compensatory liver regeneration |
| title_sort |
persistent hepatocyte apoptosis promotes tumorigenesis from diethylnitrosamine-transformed hepatocytes through increased oxidative stress, independent of compensatory liver regeneration |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/7a3c1eb510344afeaca4f3f59650deab |
| work_keys_str_mv |
AT yasutoshinozaki persistenthepatocyteapoptosispromotestumorigenesisfromdiethylnitrosaminetransformedhepatocytesthroughincreasedoxidativestressindependentofcompensatoryliverregeneration AT hayatohikita persistenthepatocyteapoptosispromotestumorigenesisfromdiethylnitrosaminetransformedhepatocytesthroughincreasedoxidativestressindependentofcompensatoryliverregeneration AT satoshitanaka persistenthepatocyteapoptosispromotestumorigenesisfromdiethylnitrosaminetransformedhepatocytesthroughincreasedoxidativestressindependentofcompensatoryliverregeneration AT kenjifukumoto persistenthepatocyteapoptosispromotestumorigenesisfromdiethylnitrosaminetransformedhepatocytesthroughincreasedoxidativestressindependentofcompensatoryliverregeneration AT makikourabe persistenthepatocyteapoptosispromotestumorigenesisfromdiethylnitrosaminetransformedhepatocytesthroughincreasedoxidativestressindependentofcompensatoryliverregeneration AT katsuhikosato persistenthepatocyteapoptosispromotestumorigenesisfromdiethylnitrosaminetransformedhepatocytesthroughincreasedoxidativestressindependentofcompensatoryliverregeneration AT yutamyojin persistenthepatocyteapoptosispromotestumorigenesisfromdiethylnitrosaminetransformedhepatocytesthroughincreasedoxidativestressindependentofcompensatoryliverregeneration AT akiradoi persistenthepatocyteapoptosispromotestumorigenesisfromdiethylnitrosaminetransformedhepatocytesthroughincreasedoxidativestressindependentofcompensatoryliverregeneration AT kazuhiromurai persistenthepatocyteapoptosispromotestumorigenesisfromdiethylnitrosaminetransformedhepatocytesthroughincreasedoxidativestressindependentofcompensatoryliverregeneration AT sadatsugusakane persistenthepatocyteapoptosispromotestumorigenesisfromdiethylnitrosaminetransformedhepatocytesthroughincreasedoxidativestressindependentofcompensatoryliverregeneration AT yoshinobusaito persistenthepatocyteapoptosispromotestumorigenesisfromdiethylnitrosaminetransformedhepatocytesthroughincreasedoxidativestressindependentofcompensatoryliverregeneration AT takahirokodama persistenthepatocyteapoptosispromotestumorigenesisfromdiethylnitrosaminetransformedhepatocytesthroughincreasedoxidativestressindependentofcompensatoryliverregeneration AT ryotarosakamori persistenthepatocyteapoptosispromotestumorigenesisfromdiethylnitrosaminetransformedhepatocytesthroughincreasedoxidativestressindependentofcompensatoryliverregeneration AT tomohidetatsumi persistenthepatocyteapoptosispromotestumorigenesisfromdiethylnitrosaminetransformedhepatocytesthroughincreasedoxidativestressindependentofcompensatoryliverregeneration AT tetsuotakehara persistenthepatocyteapoptosispromotestumorigenesisfromdiethylnitrosaminetransformedhepatocytesthroughincreasedoxidativestressindependentofcompensatoryliverregeneration |
| _version_ |
1718394581603581952 |