STAT3 defciency prevents hepatocarcinogenesis and promotes biliary proliferation in thioacetamide-induced liver injury

Mitsuhiko Abe; Takafumi Yoshida; Jun Akiba; Yu Ikezono; Fumitaka Wada; Atsutaka Masuda; Takahiko Sakaue; Toshimitsu Tanaka; Hideki Iwamoto; Toru Nakamura; Michio Sata; Hironori Koga; Akihiko Yoshimura; Takuji Torimura

doi:10.3748/wjg.v23.i37.6833

STAT3 defciency prevents hepatocarcinogenesis and promotes biliary proliferation in thioacetamide-induced liver injury

Mitsuhiko Abe, Takafumi Yoshida, Jun Akiba, Yu Ikezono, Fumitaka Wada, Atsutaka Masuda, Takahiko Sakaue, Toshimitsu Tanaka, Hideki Iwamoto, Toru Nakamura, Michio Sata, Hironori Koga, Akihiko Yoshimura, Takuji Torimura

Department of Microbiology and Immunology

Research output: Contribution to journal › Article › peer-review

7 Citations (Scopus)

Abstract

Aim To elucidate the role of STAT3 in hepatocarcinogenesis and biliary ductular proliferation following chronic liver injury. METHODS We investigated thioacetamide (TAA)-induced liver injury, compensatory hepatocyte proliferation, and hepatocellular carcinoma (HCC) development in hepatic STAT3-deficient mice. In addition, we evaluated TAAinduced biliary ductular proliferation and analyzed the activation of sex determining region Y-box9 (SOX9) and Yes-associated protein (YAP), which regulate the transdifferentiation of hepatocytes to cholangiocytes. RESULTS Both compensatory hepatocyte proliferation and HCC formation were significantly decreased in hepatic STAT3-deficient mice as compared with control mice. STAT3 deficiency resulted in augmentation of hepatic necrosis and fbrosis. On the other hand, biliary ductular proliferation increased in hepatic STAT3-defcient livers as compared with control livers. SOX9 and YAP were upregulated in hepatic STAT3-defcient hepatocytes. CONCLUSION STAT3 may regulate hepatocyte proliferation as well as transdifferentiation into cholangiocytes and serve as a therapeutic target for HCC inhibition and biliary regeneration.

Original language	English
Pages (from-to)	6833-6844
Number of pages	12
Journal	World Journal of Gastroenterology
Volume	23
Issue number	37
DOIs	https://doi.org/10.3748/wjg.v23.i37.6833
Publication status	Published - 2017 Oct 7

Keywords

Ductular reaction
Hepatocellular carcinoma
Sex determining region Y-box9
Signal transducer and activator of transcription 3
Transdifferentiation
Yesassociated protein

ASJC Scopus subject areas

Gastroenterology

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Abe, M., Yoshida, T., Akiba, J., Ikezono, Y., Wada, F., Masuda, A., Sakaue, T., Tanaka, T., Iwamoto, H., Nakamura, T., Sata, M., Koga, H., Yoshimura, A., & Torimura, T. (2017). STAT3 defciency prevents hepatocarcinogenesis and promotes biliary proliferation in thioacetamide-induced liver injury. World Journal of Gastroenterology, 23(37), 6833-6844. https://doi.org/10.3748/wjg.v23.i37.6833

STAT3 defciency prevents hepatocarcinogenesis and promotes biliary proliferation in thioacetamide-induced liver injury. / Abe, Mitsuhiko; Yoshida, Takafumi; Akiba, Jun; Ikezono, Yu; Wada, Fumitaka; Masuda, Atsutaka; Sakaue, Takahiko; Tanaka, Toshimitsu; Iwamoto, Hideki; Nakamura, Toru; Sata, Michio; Koga, Hironori; Yoshimura, Akihiko; Torimura, Takuji.

In: World Journal of Gastroenterology, Vol. 23, No. 37, 07.10.2017, p. 6833-6844.

Research output: Contribution to journal › Article › peer-review

Abe, M, Yoshida, T, Akiba, J, Ikezono, Y, Wada, F, Masuda, A, Sakaue, T, Tanaka, T, Iwamoto, H, Nakamura, T, Sata, M, Koga, H, Yoshimura, A & Torimura, T 2017, 'STAT3 defciency prevents hepatocarcinogenesis and promotes biliary proliferation in thioacetamide-induced liver injury', World Journal of Gastroenterology, vol. 23, no. 37, pp. 6833-6844. https://doi.org/10.3748/wjg.v23.i37.6833

Abe, Mitsuhiko ; Yoshida, Takafumi ; Akiba, Jun ; Ikezono, Yu ; Wada, Fumitaka ; Masuda, Atsutaka ; Sakaue, Takahiko ; Tanaka, Toshimitsu ; Iwamoto, Hideki ; Nakamura, Toru ; Sata, Michio ; Koga, Hironori ; Yoshimura, Akihiko ; Torimura, Takuji. / STAT3 defciency prevents hepatocarcinogenesis and promotes biliary proliferation in thioacetamide-induced liver injury. In: World Journal of Gastroenterology. 2017 ; Vol. 23, No. 37. pp. 6833-6844.

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abstract = "Aim To elucidate the role of STAT3 in hepatocarcinogenesis and biliary ductular proliferation following chronic liver injury. METHODS We investigated thioacetamide (TAA)-induced liver injury, compensatory hepatocyte proliferation, and hepatocellular carcinoma (HCC) development in hepatic STAT3-deficient mice. In addition, we evaluated TAAinduced biliary ductular proliferation and analyzed the activation of sex determining region Y-box9 (SOX9) and Yes-associated protein (YAP), which regulate the transdifferentiation of hepatocytes to cholangiocytes. RESULTS Both compensatory hepatocyte proliferation and HCC formation were significantly decreased in hepatic STAT3-deficient mice as compared with control mice. STAT3 deficiency resulted in augmentation of hepatic necrosis and fbrosis. On the other hand, biliary ductular proliferation increased in hepatic STAT3-defcient livers as compared with control livers. SOX9 and YAP were upregulated in hepatic STAT3-defcient hepatocytes. CONCLUSION STAT3 may regulate hepatocyte proliferation as well as transdifferentiation into cholangiocytes and serve as a therapeutic target for HCC inhibition and biliary regeneration.",

keywords = "Ductular reaction, Hepatocellular carcinoma, Sex determining region Y-box9, Signal transducer and activator of transcription 3, Transdifferentiation, Yesassociated protein",

author = "Mitsuhiko Abe and Takafumi Yoshida and Jun Akiba and Yu Ikezono and Fumitaka Wada and Atsutaka Masuda and Takahiko Sakaue and Toshimitsu Tanaka and Hideki Iwamoto and Toru Nakamura and Michio Sata and Hironori Koga and Akihiko Yoshimura and Takuji Torimura",

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T1 - STAT3 defciency prevents hepatocarcinogenesis and promotes biliary proliferation in thioacetamide-induced liver injury

AU - Abe, Mitsuhiko

AU - Yoshida, Takafumi

AU - Akiba, Jun

AU - Ikezono, Yu

AU - Wada, Fumitaka

AU - Masuda, Atsutaka

AU - Sakaue, Takahiko

AU - Tanaka, Toshimitsu

AU - Iwamoto, Hideki

AU - Nakamura, Toru

AU - Sata, Michio

AU - Koga, Hironori

AU - Yoshimura, Akihiko

AU - Torimura, Takuji

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Y1 - 2017/10/7

N2 - Aim To elucidate the role of STAT3 in hepatocarcinogenesis and biliary ductular proliferation following chronic liver injury. METHODS We investigated thioacetamide (TAA)-induced liver injury, compensatory hepatocyte proliferation, and hepatocellular carcinoma (HCC) development in hepatic STAT3-deficient mice. In addition, we evaluated TAAinduced biliary ductular proliferation and analyzed the activation of sex determining region Y-box9 (SOX9) and Yes-associated protein (YAP), which regulate the transdifferentiation of hepatocytes to cholangiocytes. RESULTS Both compensatory hepatocyte proliferation and HCC formation were significantly decreased in hepatic STAT3-deficient mice as compared with control mice. STAT3 deficiency resulted in augmentation of hepatic necrosis and fbrosis. On the other hand, biliary ductular proliferation increased in hepatic STAT3-defcient livers as compared with control livers. SOX9 and YAP were upregulated in hepatic STAT3-defcient hepatocytes. CONCLUSION STAT3 may regulate hepatocyte proliferation as well as transdifferentiation into cholangiocytes and serve as a therapeutic target for HCC inhibition and biliary regeneration.

AB - Aim To elucidate the role of STAT3 in hepatocarcinogenesis and biliary ductular proliferation following chronic liver injury. METHODS We investigated thioacetamide (TAA)-induced liver injury, compensatory hepatocyte proliferation, and hepatocellular carcinoma (HCC) development in hepatic STAT3-deficient mice. In addition, we evaluated TAAinduced biliary ductular proliferation and analyzed the activation of sex determining region Y-box9 (SOX9) and Yes-associated protein (YAP), which regulate the transdifferentiation of hepatocytes to cholangiocytes. RESULTS Both compensatory hepatocyte proliferation and HCC formation were significantly decreased in hepatic STAT3-deficient mice as compared with control mice. STAT3 deficiency resulted in augmentation of hepatic necrosis and fbrosis. On the other hand, biliary ductular proliferation increased in hepatic STAT3-defcient livers as compared with control livers. SOX9 and YAP were upregulated in hepatic STAT3-defcient hepatocytes. CONCLUSION STAT3 may regulate hepatocyte proliferation as well as transdifferentiation into cholangiocytes and serve as a therapeutic target for HCC inhibition and biliary regeneration.

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