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ARNTL2 and SERPINE1: potential biomarkers for tumor aggressiveness in colorectal cancer

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Abstract

Purpose

Cathepsin and plasmin may favor cancer cell invasion degrading extracellular matrix. Plasmin formation from plasminogen is regulated by plasminogen activator inhibitor type-1 (PAI-1). ARNTL2 activates the promoters of the PAI-1 gene, officially called SERPINE1, driving the circadian variation in circulating PAI-1 levels.

Methods

We evaluated ARNTL2 and SERPINE1 expression in 50 colorectal cancer specimens and adjacent normal tissue and in colon cancer cell lines.

Results

We found up-regulation of ARNTL2 (P = 0.004) and SERPINE1 (P = 0.002) in tumor tissue. A statistically significant association was found between high ARNTL2 mRNA levels and vascular invasion (P < 0.0001), and between high SERPINE1 mRNA levels and microsatellite instability (MSI-H and MSI-L, P = 0.025). Sorting the subjects into quartile groups, a statistically significant association was found between high ARNTL2 expression and lymph node involvement (P < 0.001), between high SERPINE1 expression and grading (P < 0.001) and between high SERPINE1 expression and MSI H–L (P < 0.0001). In SW480 cells, a more proliferative model compared to CaCo2 cells, there were higher mRNA levels of ARNTL2 (P < 0.001) and SERPINE1 (P = 0.001).

Conclusion

ARNTL2 and SERPINE1 expression is increased in colorectal cancer and in a highly proliferative colon cancer cell line and is related to tumor invasiveness and aggressiveness.

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Acknowledgments

This work was supported by “Italian Ministry of Health” grants RC0903GA51, RC1003GA52, RC1103GA47, and RC1103MI53 through Research Unit of Gastroenterology and Division of Internal Medicine, IRCCS “Casa Sollievo della Sofferenza”, San Giovanni Rotondo (FG), Italy.

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The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Division of Internal Medicine and Chronobiology Unit, IRCCS “Casa Sollievo della Sofferenza”, Research Hospital, San Giovanni Rotondo, FG, Italy

    Gianluigi Mazzoccoli

  2. Division and Laboratory of Gastroenterology, IRCCS “Casa Sollievo della Sofferenza”, Research Hospital, San Giovanni Rotondo, FG, Italy

    Valerio Pazienza, Anna Panza, Maria Rosa Valvano, Giorgia Benegiamo, Angelo Andriulli & Ada Piepoli

  3. Institute of Hepatology, Birkbeck College, London, UK

    Manlio Vinciguerra

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  1. Gianluigi Mazzoccoli
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Correspondence to Gianluigi Mazzoccoli.

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Mazzoccoli, G., Pazienza, V., Panza, A. et al. ARNTL2 and SERPINE1: potential biomarkers for tumor aggressiveness in colorectal cancer. J Cancer Res Clin Oncol 138, 501–511 (2012). https://doi.org/10.1007/s00432-011-1126-6

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