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Identifying Differentially Expressed tRNA-Derived Small Fragments as a Biomarker for the Progression and Metastasis
Hui Chen1, Zhiying Xu2, Hua Cai1
1Department of Gastroenterology, Hunan Provincial People's Hospital, The First-Affiliated Hospital of Hunan Normal University, Changsha, Hunan 410005, China.
Objectives:
The epithelial-to-mesenchymal transition (EMT) is one key step for the invasion and metastasis of colorectal cancer (CRC). Up until now, the underlying mechanism of EMT in CRC is still unpromising. Thus, it is essential to have a better understanding of its carcinogenesis. The transfer RNA-derived small fragments (tsRNAs) are a new group of small noncoding RNAs (sncRNAs), including tRNA-derived stress-induced RNAs (tiRNAs) and tRNA-derived fragments (tRFs), which have been observed to play an important role in many cancers. However, the relationship between tRFs and EMT in CRC is still unknown. Herein, we aimed to investigate the involvement of tRFs in EMT and its contribution to CRC development.
Methods:
We identified the differentially expressed tsRNAs in colorectal cancer cell line HT29 treated with TGF-β compared with control cells by using high-throughput sequencing and quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). QRT-PCR was conducted to validate the differentially expressed fragments in 68 CRC tumor samples (22 women and 46 men) and adjacent nontumor samples. The association of the expression of tRFs with CRC metastasis and clinical stage was analyzed. Meanwhile, the correlation between tRF expression and overall survival (OS) was also analyzed. TargetScan and miRanda and multiple bioinformatic approaches were used to predict the possible target genes of tsRNAs and analyze possible functions of the tRFs.
Results:
A series of differentially expressed tsRNAs were identified in TGF-β-treated HT29 cells compared with control cells. tRF-phe-GAA-031 and tRF-VAL-TCA-002 were found to be significantly upregulated in CRC tissues compared to adjacent nontumor tissues. They were significantly correlated with distant metastasis and clinical stage. We compared the differences between tumor samples and nontumor tissues from the ROC curves. The area under the ROC curve (AUC) was up to 0.7554 (95% confidence interval: 0.6739 to 0.8369, p < 0.0001) for tRF-Phe-GAA-031 and up to 0.7313 (95% confidence interval: 0.6474 to 0.8151, p < 0.0001) for tRF-VAL-TCA-002. For OS analysis, higher tRF-phe-GAA-031 and tRF-VAL-TCA-002 expressions were associated with shorter survival for CRC patients.
Conclusion:
A series of differentially expressed tsRNAs are identified in the EMT process of CRC. And tRF-phe-GAA-031 and tRF-VAL-TCA-002 are higher expressed in CRC tissues, and they might play an important role in the metastasis of CRC. Meanwhile, they may be potential biomarkers and intervention targets in the clinical treatment of CRC.
Insights
Transfer RNA-derived fragments (tRFs) are implicated in colorectal cancer (CRC) metastasis. Two specific tRFs, tRF-phe-GAA-031 and tRF-VAL-TCA-002, are upregulated in CRC tissues and associated with poorer patient survival.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Epithelial-to-mesenchymal transition (EMT) drives colorectal cancer (CRC) invasion and metastasis.
- The role of transfer RNA-derived small fragments (tsRNAs), including tRNA-derived fragments (tRFs), in CRC carcinogenesis is largely unknown.
- Understanding tsRNA involvement in EMT is crucial for advancing CRC treatment strategies.
Purpose of the Study:
- To investigate the role of tRFs in EMT within colorectal cancer.
- To identify specific tRFs associated with CRC metastasis and clinical progression.
- To explore the potential of tRFs as diagnostic or therapeutic targets in CRC.
Main Methods:
- High-throughput sequencing and qRT-PCR identified differentially expressed tsRNAs in TGF-β-treated CRC cells.
- qRT-PCR validated tsRNA expression in 68 CRC tumor and adjacent nontumor samples.
- Bioinformatic analyses predicted target genes and functions of identified tsRNAs.
Main Results:
- Several tsRNAs were differentially expressed during EMT in CRC cells.
- tRF-phe-GAA-031 and tRF-VAL-TCA-002 were significantly upregulated in CRC tissues.
- These tRFs correlated with distant metastasis, advanced clinical stage, and shorter overall survival, with ROC AUCs of 0.7554 and 0.7313, respectively.
Conclusions:
- Differentially expressed tsRNAs are identified in the EMT process of CRC.
- tRF-phe-GAA-031 and tRF-VAL-TCA-002 may promote CRC metastasis.
- These tRFs show potential as biomarkers and therapeutic targets for CRC.
