Abstract
BackgroundInvasion and metastasis are determinant events in the prognosis of Colorectal cancer (CRC), a common neoplasm worldwide. An important factor for metastasis is the acquired capacity of the cell to proliferate and invade adjacent tissues. In this paper, we explored the role of micro-RNA-26a in the regulation of proliferation and migration in CRC-derived cells through the negative regulation of PTEN, a key negative regulator of the AKT pathway.MethodsExpression levels of PTEN and mir-26a were surveyed in normal and CRC-derived cell lines; paraffin embedded human tissues, TCGA CRC expression data and a Balb/c mice orthotopic induced CRC model. CRC was induced by an initial intraperitoneal dose of the colonic carcinogen Azoxymethane followed by inflammatory promoter Dextran Sulfate Sodium Salt. Luciferase assays provide information about miR-26a–PTEN 3′UTR interaction. Proliferation and migration by real time cell analysis and wound-healing functional analyses were performed to assess the participation of mir-26a on important hallmarks of CRC and its regulation on the PTEN gene.ResultsWe observed a negative correlation between PTEN and mir-26a expression in cell lines, human tissues, TCGA data, and tissues derived from the CRC mouse model. Moreover, we showed that negative regulation of PTEN exerted by miR-26a affected AKT phosphorylation levels directly. Functional assays showed that mir-26a directly down-regulates PTEN, and that mir-26a over-expressing cells had higher proliferation and migration rates.ConclusionsAll this data proposes an important role of mir-26a as an oncomir in the progression and invasion of CRC. Our data suggested that mir-26a could be used as a biomarker of tumor development in CRC patients, however more studies must be conducted to establish its clinical role.
Highlights
Invasion and metastasis are determinant events in the prognosis of Colorectal cancer (CRC), a common neoplasm worldwide
Phosphatase and Tensin homolog (PTEN) and mir‐26a expression are inversely correlated in human CRC samples We measured mir-26a expression in CRC-derived paraffin-embedded tissue samples and found heterogeneous expression of this microRNA
PTEN was downregulated in tumors, further confirming the inverse correlation between mir-26a and PTEN that we had observed in paraffin embedded tissues samples results
Summary
Invasion and metastasis are determinant events in the prognosis of Colorectal cancer (CRC), a common neoplasm worldwide. We explored the role of micro-RNA-26a in the regulation of proliferation and migration in CRC-derived cells through the negative regulation of PTEN, a key negative regulator of the AKT pathway. Colorectal cancer (CRC) is the third most common neoplasm and the fourth cause of cancer-related death worldwide in both sexes. Invasion and metastasis are determinant events in the prognosis of CRC. One of the most relevant signaling pathways regulating cell proliferation, survival, angiogenesis, and metastasis is PI3K/ AKT; which is negatively regulated by the tumor suppressor Phosphatase and Tensin homolog (PTEN) [1]. Methylation of the PTEN promoter has been reported to be associated in high microsatellite instability in 19% of colorectal cancers [2] and the PTEN messenger has been demonstrated to be targeted by microRNA regulation [3]
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