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A circular RNA promotes tumor metastasis via stabilizing MSI2 in pancreatic ductal adenocarcinoma

ABSTRACT: In the present study, we profiled the expression of circRNAs in 10 pairs of PDAC tumors and their adjacent normal tissues, and identified circPRKD3 (hsa_circ_0000992) as a most significantly upregulated circRNAs in the tumors. Functionally, circPRKD3 overexpression promoted migration, invasion and metastasis of PDAC cells in vitro and in vivo, while knockdown of circPRKD3 showed opposite effects. Mechanistically, circPRKD3 drove metastasis via binding with the RNA-binding protein MSI2, a known oncogenic post-transcriptional regulator, and elevating MSI2 protein level in PDAC cells. The circPRKD3-MSI2 binding disrupted the interaction between MSI2 and the E3 ubiquitin ligase β-TRCP, thereby preventing the ubiquitination and degradation of MSI2. Furthermore, circPRKD3 upregulation was closed correlated to poor prognosis of PDAC patients, corresponding to the prognostic potential of MSI2 as indicated in the bioinformatic analysis. The upregulation of circPRKD3 was also observed in serum samples of PDAC patients, and combination of circPRKD3 with PDAC serum biomarkers CA199, CEA and/or CA125 increased their diagnostic efficiency. Our results suggested that circPRKD3 is a crucial metastasis-promoting circRNA in PDAC and might be a potential prognostic and diagnostic biomarker for PDAC patients.

ORGANISM(S): Homo Sapiens

SUBMITTER: Yong Peng

PROVIDER: PXD061484 | iProX | Wed Mar 05 00:00:00 GMT 2025

REPOSITORIES: iProX

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Project description:Background: There is a paucity of non-invasive markers for early detection of brain metastasis (BM) in patients with non-small cell lung cancer (NSCLC). Secretory proteomic approach based on quantitative tandem mass tag is believed to offer bright prospects for screening potential serum biomarkers for diseases. Methods: We used the secretory proteomics to identify up-regulated proteins in the highly brain metastatic cell line compared to the parental lung cancer cell line. Enzyme linked immunoassay and immunohistochemistry were performed on non-small cell lung cancer patients with brain metastasis and control samples from each cohort to verify the expression levels of candidate proteins. A logistic regression model was used to develop a biomarker panel composed of Cathepsin F (CTSF) and Fibulin-1 (FBLN1), and then an independent validation data set was used for verification. The diagnostic accuracy was evaluated by receiver operating characteristic (ROC) curve analysis. Changes in serum CTSF levels of patients were tracked to monitor the effect of treatment, and progression-free survival (PFS) and overall survival (OS) were analyzed to assess their prognostic relevance. Results: CTSF and FBLN1 levels were specifically upregulated in sera and tissues of patients with NSCLC BM. Importantly, the combined diagnostic performance of CTSF and FBLN1 was superior to their individual diagnostic performance (sensitivity and specificity). CTSF serum changes were found to reflect the therapeutic response of patients with NSCLC BM and the trends of resistance and progression were detected earlier than the MRI changes. Elevated expression of CTSF in NSCLC BM tissues was associated with poor PFS. Moreover, CTSF tissue expression was found to be an independent prognostic factor. Conclusions: CTSF and FBLN1 are potential novel and specific serum markers for early diagnosis of BM in patients with NSCLC. CTSF can also be used as a biomarker for monitoring therapeutic efficacy and prognostic assessment.

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A circular RNA promotes tumor metastasis via stabilizing MSI2 in pancreatic ductal adenocarcinoma

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