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Coordinate activation of multidrug-resistance (P-glycoprotein) genes mdr2 and mdr3 during mouse liver regeneration
L D Teeter1, J Y Chan, M T Kuo
1Department of Molecular Pathology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
Abstract:
We previously reported that only one of the three mouse multidrug-resistance (mdr) genes, mdr3, is activated in hepatocellular carcinomas (HCCs). The present study examined the expression of mdr family members during mouse liver regeneration after partial hepatectomy to determine whether the regeneration that occurs during hepatic tumorigenesis is responsible for mdr3 elevation in HCC. We demonstrated that in both C3H/HeN and B6C3/F1 mice strains, the levels of both mdr2 and mdr3 mRNAs coordinately increased five- to sevenfold 24 h after partial hepatectomy, whereas the levels of mdr1 mRNA were not statistically different from those in the controls. Forty-eight hours after partial hepatectomy, mdr mRNA levels decreased and in most cases returned to normal levels after 72 h. These results indicate that mdr3 induction during hepatocarcinogenesis is not due to liver regeneration alone.
Insights
Liver regeneration upregulates mdr2 and mdr3 mRNA but not mdr1. This suggests that liver regeneration alone does not cause the mdr3 gene activation observed in hepatocellular carcinomas (HCCs).
Area of Science:
- Hepatology
- Molecular Biology
- Cancer Research
Background:
- Hepatocellular carcinoma (HCC) is associated with the activation of the multidrug-resistance (mdr) gene mdr3.
- The role of liver regeneration in mdr gene expression during tumorigenesis is not fully understood.
Purpose of the Study:
- To investigate the expression patterns of mouse mdr family members (mdr1, mdr2, mdr3) during liver regeneration following partial hepatectomy.
- To determine if liver regeneration contributes to the elevated mdr3 expression seen in HCC.
Main Methods:
- Partial hepatectomy was performed on C3H/HeN and B6C3/F1 mice.
- Messenger RNA (mRNA) levels of mdr1, mdr2, and mdr3 were quantified at various time points post-surgery using quantitative methods.
- Gene expression levels were compared to control groups.
Main Results:
- mdr2 and mdr3 mRNA levels significantly increased (5- to 7-fold) 24 hours after partial hepatectomy in both mouse strains.
- mdr1 mRNA levels showed no statistically significant change compared to controls.
- mdr mRNA levels returned to baseline within 72 hours post-hepatectomy.
Conclusions:
- Liver regeneration induces a coordinate upregulation of mdr2 and mdr3 mRNA.
- The observed mdr3 gene activation in hepatocellular carcinoma is not solely attributable to the regenerative processes of the liver.