| Autor: |
Kumiko Tanaka, Jinsei Miyoshi, Miwako Kagawa, Shinji Kitamura, Noriaki Murayama, Yasuyuki Okada, Hironori Tanaka, Tetsu Tomonari, Satoshi Teramae, Naoki Muguruma, Koichi Okamoto, Yasushi Sato, Yoshihiko Miyamoto, Yasuhiro Mitsui, Keiichiro Matsumura, Yasuteru Fujino, Takahiro Tanaka, Tetsuji Takayama, Hiroshi Miyamoto |
| Rok vydání: |
2019 |
| Předmět: |
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| Zdroj: |
Annals of Oncology. 30:vi105 |
| ISSN: |
0923-7534 |
| DOI: |
10.1093/annonc/mdz338.066 |
| Popis: |
Background Rectal neuroendocrine tumors (NETs) are the most common of GI NETs, growing in incidence. Though NETs are capable of invasion and metastasis regardless of size, currently there is no molecular marker to predict them. Accumulating evidence indicates that miRNAs have been implicated as key regulators of carcinogenesis. Aim: We sought to develop a miRNA-based signature to predict rectal NETs invasion and metastasis using comprehensive miRNA-based analysis and examined its performance. We also analyzed associated mechanisms. Methods: We performed miRNA microarray using small (≤1cm) rectal NETs tissues resected endoscopically to compare lymphovascular invasion (LVI)(+) (n = 7) vs. LVI(-) (n = 7). Candidate miRNAs were assessed by qRT-PCR in an independent cohort (n = 10). We then evaluated the diagnostic performance of the marker by qRT-PCR for the other independent cohort (n = 22). Finally, we examined its metastasis-promoting mechanisms by pathway analysis program and in-vitro experiments using NET cell line H727. Results: Initially, we identified 5 most over-expressed miRNAs in LVI, of which miR-144/451 were successfully validated in an alternative cohort. The miRNA signature (miR-144/451) was able to accurately discriminate LVI patients (AUC=0.75; Sens:80%, Spec:82%). Mechanistically, we revealed miR-144/451 directly targeted PTEN/p19 and validated by immunohistochemistry. Transfection of miR-144/451 mimics into NET cells significantly increased invasion and migration. Similarly, knockdown of PTEN/p19 with siRNAs in NET cells significantly increased them. Conclusion: Using systematic and comprehensive biomarker discovery approach, we have developed and successfully validated the first novel and robust miRNA signature to detect rectal NETs invasion and metastasis and demonstrated the underlying mechanisms for invasion and metastasis. These data highlights great potential for not only the biomarker-guided treatment strategy, but therapeutic targets for rectal NET. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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