Reduced Hepatocyte Proliferation is the Basis of Retarded Liver Tumor Progression and Liver Regeneration in Mice Lacking N-Acetylglucosaminyltransferase III

Xiaoping Yang, Jian Tang, Charles E. Rogler, Pamela Stanley

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Abstract

Mice lacking N-acetylglucosaminyltransferase III (GlcNAc-TIII) exhibit slightly but significantly retarded liver tumor progression after a single injection of 10 μg/g diethylnitrosamine (DEN) and continued administration of phenobarbital (PB) in drinking water. A key question is whether the absence of GlcNAc-TIII inhibits cell proliferation or induces apoptosis. Because PB aids tumor progression, we tested whether it diminished the difference in tumor progression between Mgat3+/+ and Mgat3Δ/Δ mice. Here, we show that in the absence of PB, control males developed about twice as many liver tumor nodules as males lacking GlcNAc-TIII. Both the size of liver tumors and liver weights were significantly greater in DEN-treated wild-type or heterozygous mice. Apoptosis assays performed monthly after DEN treatment showed no differences between mutant and wild-type. However, there was a marked retardation in liver regeneration after partial (70%) hepatectomy (PH). Wild-type mice incorporated bromodeoxyuridine in ∼15% of hepatocyte nuclei at 48 h after PH, whereas mice lacking GlcNAc-TIII had only ∼5% positive nuclei. This was not because of enhanced apoptosis in mutant mice after PH. Expression of the Mgat3 gene remained undetectable in wild-type liver by Northern analysis after tumor induction or after PH. In addition, transgenic overexpression of GlcNAc-TIII in hepatocytes did not enhance tumor progression in Mgat3Δ/Δ mice, and there were no differences in tumor progression or liver regeneration after PH between control and transgenic mice overexpressing GlcNAc-TIII in liver. Therefore, the nonhepatic action of GlcNAc-TIII promotes hepatocyte proliferation after PH, as well as the progression of DEN-induced tumors, providing evidence for a functional role of the bisecting GlcNAc on circulating glycoprotein growth factor(s) that stimulate hepatocyte proliferation.

Original languageEnglish (US)
Pages (from-to)7753-7759
Number of pages7
JournalCancer Research
Volume63
Issue number22
StatePublished - Nov 15 2003

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beta-1,4-mannosyl-glycoprotein beta-1,4-N-acetylglucosaminyltransferase
Liver Regeneration
Hepatocytes
Diethylnitrosamine
Liver
Neoplasms
Phenobarbital
Apoptosis
Hepatectomy
Bromodeoxyuridine
Tumor Burden
Drinking Water
Transgenic Mice

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Reduced Hepatocyte Proliferation is the Basis of Retarded Liver Tumor Progression and Liver Regeneration in Mice Lacking N-Acetylglucosaminyltransferase III. / Yang, Xiaoping; Tang, Jian; Rogler, Charles E.; Stanley, Pamela.

In: Cancer Research, Vol. 63, No. 22, 15.11.2003, p. 7753-7759.

Research output: Contribution to journalArticle

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title = "Reduced Hepatocyte Proliferation is the Basis of Retarded Liver Tumor Progression and Liver Regeneration in Mice Lacking N-Acetylglucosaminyltransferase III",
abstract = "Mice lacking N-acetylglucosaminyltransferase III (GlcNAc-TIII) exhibit slightly but significantly retarded liver tumor progression after a single injection of 10 μg/g diethylnitrosamine (DEN) and continued administration of phenobarbital (PB) in drinking water. A key question is whether the absence of GlcNAc-TIII inhibits cell proliferation or induces apoptosis. Because PB aids tumor progression, we tested whether it diminished the difference in tumor progression between Mgat3+/+ and Mgat3Δ/Δ mice. Here, we show that in the absence of PB, control males developed about twice as many liver tumor nodules as males lacking GlcNAc-TIII. Both the size of liver tumors and liver weights were significantly greater in DEN-treated wild-type or heterozygous mice. Apoptosis assays performed monthly after DEN treatment showed no differences between mutant and wild-type. However, there was a marked retardation in liver regeneration after partial (70{\%}) hepatectomy (PH). Wild-type mice incorporated bromodeoxyuridine in ∼15{\%} of hepatocyte nuclei at 48 h after PH, whereas mice lacking GlcNAc-TIII had only ∼5{\%} positive nuclei. This was not because of enhanced apoptosis in mutant mice after PH. Expression of the Mgat3 gene remained undetectable in wild-type liver by Northern analysis after tumor induction or after PH. In addition, transgenic overexpression of GlcNAc-TIII in hepatocytes did not enhance tumor progression in Mgat3Δ/Δ mice, and there were no differences in tumor progression or liver regeneration after PH between control and transgenic mice overexpressing GlcNAc-TIII in liver. Therefore, the nonhepatic action of GlcNAc-TIII promotes hepatocyte proliferation after PH, as well as the progression of DEN-induced tumors, providing evidence for a functional role of the bisecting GlcNAc on circulating glycoprotein growth factor(s) that stimulate hepatocyte proliferation.",
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