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. 2021 Jul 17;20(1):95.
doi: 10.1186/s12943-021-01389-5.

A novel class of tsRNA signatures as biomarkers for diagnosis and prognosis of pancreatic cancer

Fangfang Jin #  1 , Liuqing Yang #  2 , Weixiang Wang #  3 , Na Yuan  1 , Shoubin Zhan  3 , Ping Yang  4 , Xi Chen  5 , Tonghui Ma  6 , Yanbo Wang  7
Affiliations

A novel class of tsRNA signatures as biomarkers for diagnosis and prognosis of pancreatic cancer

Fangfang Jin et al. Mol Cancer. .
No abstract available

Keywords: Biomarker; Pancreatic cancer; tsRNA.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Identification of novel tsRNA biomarkers from serum samples of PC patients. A Proportion of changed miRNAs and tsRNAs in serum from PC patients compared with normal controls. B The scatter plot figuratively expresses the changes in tsRNAs expression. C Hierarchical clustering indicates the differences in tsRNA expression profiling between two groups. D The six serum tsRNAs expression in PC patients in the training set. Serum samples from 24 PC patients and 24 controls were collected and subjected to qRT-PCR absolute quantification. E qRT-PCR shows the concentrations of tRF-Pro-AGG-004 and tRF-Leu-CAG-002 in 150 PC patients and 100 control individuals enrolled in the validation set. F ROC curves of tRF-Pro-AGG-004 and tRF-Leu-CAG-002 concentrations in serum samples from PC patients versus healthy controls. G Comparison of the diagnostic values of 2-tsRNA signature with CA19-9 and CEA in pancreatic cancer. H ROC analysis estimates the diagnostic value of 2-tsRNA signature in early stage pancreatic cancer. I qRT-PCR shows the serum concentrations of tRF-Pro-AGG-004 and tRF-Leu-CAG-002 in other types of diseases [including 31 PC patients, 48 HCC patients, 60 breast cancer (BRC) patients, 53 non-small cell lung cancer patients (NSCLC), 23 hepatocirrhosis patients, 24 hepatitis patients and 48 control individuals]. **P < 0.01, ***P < 0.001, ****P < 0.0001
Fig. 2
Fig. 2
Elevated tsRNAsin tumor tissues as independent indicator for predicting survival time of PC patients. A tRF-Pro-AGG-004 and tRF-Leu-CAG-002 expression in PC tissues and paired serum from the same patients (n = 20). B The concentrations of tRF-Pro-AGG-004 and tRF-Leu-CAG-002 secreted in the PANC1 culture medium depend on cell number and duration of culture. C PANC1 cells were treatmented with tRF-Pro-AGG-004 or tRF-Leu-CAG-002 inhibitors, the concentrations of tRF-Pro-AGG-004 and tRF-Leu-CAG-002 secreted in the PANC1 culture medium were measured. D Serum tRF-Pro-AGG-004 and tRF-Leu-CAG-002 expression levels in normal mice and PC orthotopic transplantation tumor mice. E Significant correlation between serum tRF-Pro-AGG-004 and tRF-Leu-CAG-002 expression and tumor weight in mice. F tRF-Pro-AGG-004 in patient serum, mouse serum and cell medium is mainly in exosome-free fraction, whereas tRF-Leu-CAG-002 is mainly in exosome. The 60 PC patients in cohort 1 were divided into two groups: shorter-survival group (n = 30) and longer survival group (n = 30). The 75 PC patients in cohort 2 were divided into two groups: shorter-survival group (n = 38) and longer survival group (n = 37). G Representative results for in situ hybridization (ISH) staining of tRF-Pro-AGG-004 or tRF-Leu-CAG-002 in pancreatic cancer (PC) tissues from two groups. H, J ISH scores of tRF-Pro-AGG-004 and tRF-Leu-CAG-002 in two groups from two cohorts (according to positive rate of ISH staining, each sample was scored as 1(0–25%), 2(26–50%), 3(51–75%), 4(76–100%)). I, K Kaplan–Meier overall survival curve of PC patients in two cohorts based on ISH scores of tRF-Pro-AGG-004 and tRF-Leu-CAG-002, and combined tRF-Pro-AGG-004 and tRF-Leu-CAG-002. The optimal cut-offs of ISH was set (ISH score ≥ 3 as high and ISH score < 3 as low). *P < 0.05; **P < 0.01; ****P < 0.0001
Fig. 3
Fig. 3
The production mechanisms and biological functions of the two tsRNAs. A Representative images (left) and statistics analysis (right) of ANG staining from 60 PC tissues (PC) and 60 matched normal adjacent tissue (N). B TCGA dataset analysis of ANG in 179 pancreatic cancerous tissues (PC) and 171 normal pancreatic tissues (Normal). C For survival analyses, IHC intensities of ANG protein in PC tissues and paired normal adjacent tissues (n = 60) were collected and analyzed based on the ratio of IHC intensities (PC tissues/ paired normal adjacent tissues). The median of the data set was calculated as 1.11. And the median value 1.11 was set as cut-off value, > 1.11 as high expression and ≤ 1.11 as low expression. D PANC1 cells were transfected with control siRNA or ANG siRNA. Total RNA was extracted and subjected to qRT-PCR detection of tRF-Pro-AGG-004 and tRF-Leu-CAG-002. E-I Intravenous injection of ANG siRNA inhibited tumor growth and tsRNAs expression in vivo. E Flow chart of the experimental design. The PC orthotopic transplantation model was constructed using PAN02 cells in C57BL/6 J mice. Then the mice were randomly divided into two groups and intravenous delivered cholesterol-modified ANG siRNA (ANG-si) or control siRNA (si-CTL) every 3 days for 4 weeks (7 mice/group). F Tumor image at the day 28. G Quantitative analysis of tumor weights. H, I Quantitative analysis of two tsRNAs levels in tumor and serum in mice from two groups. J-O tRF-Pro-AGG-004 and tRF-Leu-CAG-002 function in pancreatic cancer. J Flow chart of the experimental design. PANC1 cells infected with control lentivirus (Normal), tRF-Pro-AGG-004 and tRF-Leu-CAG-002 overexpression lentivirus (tsRNAs) were implanted subcutaneously into nude mice (5 mice/group), and tumor growth was evaluated on day 30 after implantation. K Tumor images. L, M Quantitative analysis of tumor weights and tumor volumes. N, O Representative images and histogram statistics from EdU and invasion assays of PANC1 cells transfected with tsRNA mimics or inhibitors. *P < 0.05; **P < 0.01; ****P < 0.0001
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