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Small tRNA-derived RNAs are increased and more abundant than microRNAs in chronic hepatitis B and C.

Selitsky SR, Baran-Gale J, Honda M, Yamane D, Masaki T, Fannin EE, Guerra B, Shirasaki T, Shimakami T, Kaneko S, Lanford RE, Lemon SM, Sethupathy P - Sci Rep (2015)

Bottom Line: In contrast, in matched cancer tissue, 5' tRH abundance was reduced, and relative abundance of individual 5' tRHs was altered.In hepatitis B-associated HCC, 5' tRH abundance correlated with expression of the tRNA-cleaving ribonuclease, angiogenin.These results demonstrate that tRHs are the most abundant small RNAs in chronically infected liver and that their abundance is altered in liver cancer.

View Article: PubMed Central - PubMed

Affiliation: 1] Bioinformatics and Computational Biology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America [2] Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America [3] Departments of Medicine and Microbiology &Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America [4] Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.

ABSTRACT
Persistent infections with hepatitis B virus (HBV) or hepatitis C virus (HCV) account for the majority of cases of hepatic cirrhosis and hepatocellular carcinoma (HCC) worldwide. Small, non-coding RNAs play important roles in virus-host interactions. We used high throughput sequencing to conduct an unbiased profiling of small (14-40 nts) RNAs in liver from Japanese subjects with advanced hepatitis B or C and hepatocellular carcinoma (HCC). Small RNAs derived from tRNAs, specifically 30-35 nucleotide-long 5' tRNA-halves (5' tRHs), were abundant in non-malignant liver and significantly increased in humans and chimpanzees with chronic viral hepatitis. 5' tRH abundance exceeded microRNA abundance in most infected non-cancerous tissues. In contrast, in matched cancer tissue, 5' tRH abundance was reduced, and relative abundance of individual 5' tRHs was altered. In hepatitis B-associated HCC, 5' tRH abundance correlated with expression of the tRNA-cleaving ribonuclease, angiogenin. These results demonstrate that tRHs are the most abundant small RNAs in chronically infected liver and that their abundance is altered in liver cancer.

No MeSH data available.


Related in: MedlinePlus

5′ tRH abundance in HBV- and HCV-associated hepatocellular carcinoma.(b) Abundance (RT-qPCR) of (left) 5′ tRHGly (Gly[C/G]CC) and (right) 5′ tRHVal (Val[A/C]AC) in (top) non-malignant (n = 9) and cancer tissue (n = 10) from HBV-infected subjects, and (bottom) non-malignant (n = 14), and cancer tissue (n = 15) from HCV-infected subjects. Box and whisker plots are overlaid with data from each sample; whiskers extend to 1.5 * interquartile range. P-values calculated using Mann-Whitney U-test. *P < 0.05; **P < 0.01; ***P < 0.005. (b) Proportion of mapped reads aligning to tRNAs for the paired cancer and non-cancer tissue from subjects with chronic hepatitis B (n = 3) and hepatitis C (n = 4) (c) Correlation heatmap of tRNA-derived RNA expression profiles determined by small RNA sequencing. The colors of the cells represent Spearman's rank correlation coefficients of the relative levels of the 10 most abundant tRNA-derived RNAs between all pairs of tissue samples sequenced (n = 20). (d) Proportion of mapped reads that align to 5′ tRHGly and 5′ tRHVal in non-malignant and cancer tissue from (top) HBV-infected and (bottom) HCV-infected subjects. “Mapped reads” represents all reads aligning to miRNAs or tRNAs (see Methods).
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f2: 5′ tRH abundance in HBV- and HCV-associated hepatocellular carcinoma.(b) Abundance (RT-qPCR) of (left) 5′ tRHGly (Gly[C/G]CC) and (right) 5′ tRHVal (Val[A/C]AC) in (top) non-malignant (n = 9) and cancer tissue (n = 10) from HBV-infected subjects, and (bottom) non-malignant (n = 14), and cancer tissue (n = 15) from HCV-infected subjects. Box and whisker plots are overlaid with data from each sample; whiskers extend to 1.5 * interquartile range. P-values calculated using Mann-Whitney U-test. *P < 0.05; **P < 0.01; ***P < 0.005. (b) Proportion of mapped reads aligning to tRNAs for the paired cancer and non-cancer tissue from subjects with chronic hepatitis B (n = 3) and hepatitis C (n = 4) (c) Correlation heatmap of tRNA-derived RNA expression profiles determined by small RNA sequencing. The colors of the cells represent Spearman's rank correlation coefficients of the relative levels of the 10 most abundant tRNA-derived RNAs between all pairs of tissue samples sequenced (n = 20). (d) Proportion of mapped reads that align to 5′ tRHGly and 5′ tRHVal in non-malignant and cancer tissue from (top) HBV-infected and (bottom) HCV-infected subjects. “Mapped reads” represents all reads aligning to miRNAs or tRNAs (see Methods).

Mentions: In HCC tissue from HBV-infected subjects, RT-qPCR analysis showed that 5′ tRHGly and 5′ tRHVal abundance was significantly reduced (P<0.005 for both) (Figure 2a). Similar reductions were evident in HCV-associated cancer tissue, but significant only for 5′ tRHVal (P<0.05). We then sequenced small RNAs in cancer tissue from 4 HBV- and 4 HCV-infected subjects. The proportion of reads mapping to tRNA genes was reduced in 4 of 7 samples for which a paired analysis with non-malignant liver was possible, and relatively unchanged in the other 3 (Figure 2b). Although tRNA-derived RNA expression profiles were similar across non-malignant tissues from different subjects, there was substantial variation when compared to cancer tissues (Figure 2c). This suggests that the relative abundance of specific tRNA-derived RNAs is altered in HCC. Notably, the relative abundance of 5′ tRHGly was reduced by ~50–60% in both HBV- and HCV-associated cancer (Figure 2d).


Small tRNA-derived RNAs are increased and more abundant than microRNAs in chronic hepatitis B and C.

Selitsky SR, Baran-Gale J, Honda M, Yamane D, Masaki T, Fannin EE, Guerra B, Shirasaki T, Shimakami T, Kaneko S, Lanford RE, Lemon SM, Sethupathy P - Sci Rep (2015)

5′ tRH abundance in HBV- and HCV-associated hepatocellular carcinoma.(b) Abundance (RT-qPCR) of (left) 5′ tRHGly (Gly[C/G]CC) and (right) 5′ tRHVal (Val[A/C]AC) in (top) non-malignant (n = 9) and cancer tissue (n = 10) from HBV-infected subjects, and (bottom) non-malignant (n = 14), and cancer tissue (n = 15) from HCV-infected subjects. Box and whisker plots are overlaid with data from each sample; whiskers extend to 1.5 * interquartile range. P-values calculated using Mann-Whitney U-test. *P < 0.05; **P < 0.01; ***P < 0.005. (b) Proportion of mapped reads aligning to tRNAs for the paired cancer and non-cancer tissue from subjects with chronic hepatitis B (n = 3) and hepatitis C (n = 4) (c) Correlation heatmap of tRNA-derived RNA expression profiles determined by small RNA sequencing. The colors of the cells represent Spearman's rank correlation coefficients of the relative levels of the 10 most abundant tRNA-derived RNAs between all pairs of tissue samples sequenced (n = 20). (d) Proportion of mapped reads that align to 5′ tRHGly and 5′ tRHVal in non-malignant and cancer tissue from (top) HBV-infected and (bottom) HCV-infected subjects. “Mapped reads” represents all reads aligning to miRNAs or tRNAs (see Methods).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4286764&req=5

f2: 5′ tRH abundance in HBV- and HCV-associated hepatocellular carcinoma.(b) Abundance (RT-qPCR) of (left) 5′ tRHGly (Gly[C/G]CC) and (right) 5′ tRHVal (Val[A/C]AC) in (top) non-malignant (n = 9) and cancer tissue (n = 10) from HBV-infected subjects, and (bottom) non-malignant (n = 14), and cancer tissue (n = 15) from HCV-infected subjects. Box and whisker plots are overlaid with data from each sample; whiskers extend to 1.5 * interquartile range. P-values calculated using Mann-Whitney U-test. *P < 0.05; **P < 0.01; ***P < 0.005. (b) Proportion of mapped reads aligning to tRNAs for the paired cancer and non-cancer tissue from subjects with chronic hepatitis B (n = 3) and hepatitis C (n = 4) (c) Correlation heatmap of tRNA-derived RNA expression profiles determined by small RNA sequencing. The colors of the cells represent Spearman's rank correlation coefficients of the relative levels of the 10 most abundant tRNA-derived RNAs between all pairs of tissue samples sequenced (n = 20). (d) Proportion of mapped reads that align to 5′ tRHGly and 5′ tRHVal in non-malignant and cancer tissue from (top) HBV-infected and (bottom) HCV-infected subjects. “Mapped reads” represents all reads aligning to miRNAs or tRNAs (see Methods).
Mentions: In HCC tissue from HBV-infected subjects, RT-qPCR analysis showed that 5′ tRHGly and 5′ tRHVal abundance was significantly reduced (P<0.005 for both) (Figure 2a). Similar reductions were evident in HCV-associated cancer tissue, but significant only for 5′ tRHVal (P<0.05). We then sequenced small RNAs in cancer tissue from 4 HBV- and 4 HCV-infected subjects. The proportion of reads mapping to tRNA genes was reduced in 4 of 7 samples for which a paired analysis with non-malignant liver was possible, and relatively unchanged in the other 3 (Figure 2b). Although tRNA-derived RNA expression profiles were similar across non-malignant tissues from different subjects, there was substantial variation when compared to cancer tissues (Figure 2c). This suggests that the relative abundance of specific tRNA-derived RNAs is altered in HCC. Notably, the relative abundance of 5′ tRHGly was reduced by ~50–60% in both HBV- and HCV-associated cancer (Figure 2d).

Bottom Line: In contrast, in matched cancer tissue, 5' tRH abundance was reduced, and relative abundance of individual 5' tRHs was altered.In hepatitis B-associated HCC, 5' tRH abundance correlated with expression of the tRNA-cleaving ribonuclease, angiogenin.These results demonstrate that tRHs are the most abundant small RNAs in chronically infected liver and that their abundance is altered in liver cancer.

View Article: PubMed Central - PubMed

Affiliation: 1] Bioinformatics and Computational Biology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America [2] Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America [3] Departments of Medicine and Microbiology &Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America [4] Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.

ABSTRACT
Persistent infections with hepatitis B virus (HBV) or hepatitis C virus (HCV) account for the majority of cases of hepatic cirrhosis and hepatocellular carcinoma (HCC) worldwide. Small, non-coding RNAs play important roles in virus-host interactions. We used high throughput sequencing to conduct an unbiased profiling of small (14-40 nts) RNAs in liver from Japanese subjects with advanced hepatitis B or C and hepatocellular carcinoma (HCC). Small RNAs derived from tRNAs, specifically 30-35 nucleotide-long 5' tRNA-halves (5' tRHs), were abundant in non-malignant liver and significantly increased in humans and chimpanzees with chronic viral hepatitis. 5' tRH abundance exceeded microRNA abundance in most infected non-cancerous tissues. In contrast, in matched cancer tissue, 5' tRH abundance was reduced, and relative abundance of individual 5' tRHs was altered. In hepatitis B-associated HCC, 5' tRH abundance correlated with expression of the tRNA-cleaving ribonuclease, angiogenin. These results demonstrate that tRHs are the most abundant small RNAs in chronically infected liver and that their abundance is altered in liver cancer.

No MeSH data available.


Related in: MedlinePlus