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. 2018 Jan 1:17:1533034618756785.
doi: 10.1177/1533034618756785.

Identification of the Differential Expression Profiles of Serum and Tissue Proteins During Rat Hepatocarcinogenesis

Xia Sheng  1 , Tao Huang  2 , Jianmin Qin  2   3 , Lin Yang  2 , Zhong-Qiu Sa  2 , Qi Li  4
Affiliations

Identification of the Differential Expression Profiles of Serum and Tissue Proteins During Rat Hepatocarcinogenesis

Xia Sheng et al. Technol Cancer Res Treat. .

Abstract

The pathogenesis of hepatocellular carcinoma is complex and not fully known yet. This study aims to screen and identify the differentially expressed proteins in peripheral blood and liver tissue samples from rat hepatocellular carcinoma and to further clarify the pathogenesis and discover the specific tumor markers and molecular targets of hepatocellular carcinoma. The hepatocellular carcinoma model of Wistar rats were induced by chemical carcinogen. The serum and liver tissue samples were obtained after induction for 2, 4, 8, 14, 18, and 21 weeks. The results showed that the clusterin (IPI00198667), heat shock protein a8 (IPI00208205), and N-myc downstream-regulated gene-2 (IPI00382069) being closely related to hepatocarcinogenesis were eventually identified from the 30 different proteins. As the time progressed, the serum levels of clusterin and heat shock protein a8 increased gradually during induced liver cancer in rats. However, the serum N-myc downstream-regulated gene 2 level in induced liver cancer in rats underwent biphasic changes, and the serum N-myc downstream-regulated gene 2 level decreased at the 8th week, increased at the 14th week, and then decreased significantly. Statistical difference occurred in protein expression of clusterin and heat shock protein a8 in liver tissues at the different time points. In the liver tissues, the N-myc downstream-regulated gene 2 level decreased gradually at the 8th week, increased gradually at the 14th week, and then decreased significantly after 14 weeks. The study demonstrated that heat shock protein a8, clusterin, and N-myc downstream-regulated gene 2 participated in the process of abnormal cell division, proliferation, and carcinogenesis of liver cells during hepatocarcinogenesis.

Keywords: diagnosis; hepatocellular carcinoma (HCC); occurrence; proteomics; target therapy.

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Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Morphological changes and tissue pathology of liver tissues during induced liver cancer in rats. A, The volume of liver lobe became swollen and large at the eighth week, and the liver surface had many white nodules. B, Hepatocytes occurred obviously nucleolus atypia, structure disorder, and canceration (original magnification HE ×200). C, The volume of liver lobe became obviously swollen and larger at the 14th week, and the liver surface showed large tumor lesions. D, Hepatocytes had a lot of large nucleolus, and some hepatocytes became cancer cells (original magnification HE ×200). E, Many tumor lesions occurred in liver tissues at the 18th week. F, Liver tissues had structure disorder and a lot of cancer cells and became typical pathological manifestations of hepatocellular carcinoma (original magnification HE ×200). G, Many tumor lesions occurred in liver tissues at the 21st week, and there were a lot of tumor vessels and mecrotic lesions on the surface of tumor tissues. H, Hepatocytes had typical nucleolus atypia, structure disorder, and intracytoplasmic vacuoles degeneration. The histopathological manifestations were typical hepatocellular carcinoma (original magnification HE ×200).
Figure 2.
Figure 2.
Serum 2-dimensional gel electrophoresis at the different time points during induced liver cancer in rats. A, Serum 2-dimensional gel electrophoresis in normal control rats. B, Serum 2-dimensional gel electrophoresis at the fourth week during induced liver cancer in rats. C, Serum 2-dimensional gel electrophoresis at the 14th week during induced liver cancer in rats. D, Serum 2-dimensional gel electrophoresis at the 21st week during induced liver cancer in rats.
Figure 3.
Figure 3.
Two-dimensional gel electrophoresis of liver tissues at the different time points during induced liver cancer in rats. A, Two-dimensional gel electrophoresis of liver tissue at the fourth week during induced liver cancer in rats. B, Two-dimensional gel electrophoresis of liver tissue at the 14th week during induced liver cancer in rats. C, Two-dimensional gel electrophoresis of liver tissue at the 21st week during induced liver cancer in rats. D, Two-dimensional gel electrophoresis of paraneoplastic liver tissue at the 21st week during induced liver cancer in rats.
Figure 4.
Figure 4.
The serum level of clusterin during induced liver cancer in rats. The curve chart showed that as the time prolonged, the serum level of clusterin increased gradually compared to the control group.
Figure 5.
Figure 5.
The serum level of heat shock protein a8 (HSPa8) during induced liver cancer in rats. The curve chart showed that as the time prolonged, the serum level of HSPa8 increased gradually compared to the control group.
Figure 6.
Figure 6.
The serum level of N-myc downstream-regulated gene-2 (NDRG2) during induced liver cancer in rats. The curve chart showed that as the time prolonged, the serum level of NDRG2 underwent biphasic changes, and the serum NDRG2 level decreased gradually from 2 to 8 weeks, increased gradually from 8 to 14 weeks, and then decreased significantly after 14 weeks.
Figure 7.
Figure 7.
The protein expression of clusterin and heat shock protein a8 (HSPa8) in liver tissues at the different time points didn’t show statistical difference. The N-myc downstream-regulated gene-2 (NDRG2) level in liver tissues decreased gradually at the eighth week, increased gradually at the 14th week, and then decreased significantly after 14 weeks; this indicated that the NDRG2 expression showed biphasic changes in liver tissues at the different time points.
Figure 8.
Figure 8.
The location of expression of clusterin in liver tissues during induced liver cancer in rats (IHC ×200). A, The expression of clusterin in the cytoplasm of hepatocytes was weakly positive in liver parenchyma at the second week. B, The expression of clusterin in the cytoplasm of hepatocytes was positive around the portal area at the fourth week. C, The expression of clusterin in the cytoplasm of hepatocytes was strongly positive around the portal area at the eighth week. D and E, The expression of clusterin in the cytoplasm of hepatocytes was weakly positive in liver parenchyma at the 14th and 18th week. F, The expression of clusterin in cytoplasm of hepatocytes was strongly positive in liver parenchyma at the 21st week.
Figure 9.
Figure 9.
The location of expression of heat shock protein a8 (HSPa8) in liver tissues during induced liver cancer in rats (IHC ×200). (A): The expression of HSPa8 in the cytoplasm of hepatocytes was positive in liver parenchyma at the second week. B and C, The expression of HSPa8 in the cytoplasm of hepatocytes was strongly positive in liver parenchyma at the fourth and eighth weeks. D, The expression of HSPa8 in the cytoplasm of hepatocytes was strongest positive in liver parenchyma at the 14th week. E and F, The expression of HSPa8 in cytoplasm of hepatocytes was strongly positive in liver parenchyma at the 18th and 21st weeks.
Figure 10.
Figure 10.
The location of expression of N-myc downstream-regulated gene-2 (NDRG2) in liver tissues during induced liver cancer in rats (IHC ×200). A, The expression of NDRG2 in the cytoplasm and nucleus of mesenchymal cells occurred around portal area at the second week. B and C, The expression of NDRG2 in cytoplasm and nucleus of hepatocytes was strongly positive in liver parenchyma at the fourth and eighth week. D- F, The expression of NDRG2 in cytoplasm and nucleus of hepatocytes was weakly positive in liver parenchyma after the 14th week.
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