Increased expression of system large amino acid transporter (LAT)-1 mRNA is associated with invasive potential and unfavorable prognosis of human clear cell renal cell carcinoma

Abstract

Background: The system L amino acid transporter (LAT) has an important role in the transport of various amino acids, and there have been reports about the relation of this system to cancer. Although LATs are highly expressed in the kidneys, little is known about their influence on human renal cancer.

Methods: To clarify the role of LATs in human clear cell renal cell carcinoma (RCC), we investigated the expression of mRNAs for LAT1, LAT2, LAT3, LAT4, and 4F2hc in clear cell RCC tissues. The mRNAs of these five genes were analyzed by the real-time reverse transcription polymerase chain reaction in matched sets of tumor and non-tumor tissues obtained at operation from 82 Japanese patients with clear cell RCC. We also measured phosphorylated S6 ribosomal protein (Ser-235/236) proteins levels in 18 paired tumor and non-tumor tissues of the patients by Western blotting.

Results: Expression of LAT1 mRNA was significantly increased in tumor tissue compared with non-tumor tissue, while expression of LAT2 and LAT3 mRNAs was reduced. There was no difference in the expression of LAT4 and 4F2hc mRNAs between tumor and non-tumor tissues. Increased expression of LAT1 mRNA was associated with less differentiated tumors, local invasion, microscopic vascular invasion, and metastasis. Kaplan-Meier survival analysis showed that a higher serum LAT1 mRNA level was associated with a shorter overall survival time. Phosphorylated S6 ribosomal protein levels were associated with metastatic potential. LAT1 mRNA levels positively correlated with phosphorylated S6 ribosomal protein proteins levels in primary tumors.

Conclusions: These findings suggest that LAT1 mRNA is related to the invasive and progressive potential of clear cell RCC.

Figure 1

LATs mRNA expressions between tumor and non-tumor tissues in human clear cell renal cell carcinoma. a; LAT1, b; LAT2, c; LAT3, d; LAT4, e; 4F2hc. The data show the 95% confidential interval.

Figure 2

LAT1 mRNAs in tumors. a; grade. b; pT stage. c; microscopic vascular invasion. d; metastasis. The data show the 95% confidential interval.

Figure 3

Expression of phosphorylated S6 ribosomal protein (Ser-235/236) (32 kDa) and beta actin (42 kDa) proteins in the primary tumor tissues using Western blotting. M; marker. N; non-tumor tissue. T; primary tumor tissue with metastatic lesions. Each number corresponds to a case number.

Figure 4

Expression of phosphorylated S6 ribosomal protein (Ser-235/236). a; tumor. b; grade. c; pT stage. d; microscopic vascular invasion. e; metastasis. The data show the 95% confidential interval.

Figure 5

Spearman rank correlation coefficient relationship. X axis is an independent variable. Y axis is a dependent variable. LAT1 mRNA levels positively correlated with phosphorylated S6 ribosomal protein (Ser-235/236) levels in primary tumor tissues.

Figure 6

Survival curve based on the median values of mRNA expression of LATs in tumors, the cases were divided into two groups at this levels high and low expression. a; LAT1, b; LAT2, c; LAT3, d; LAT4, e; 4F2hc.