Abstract
Hypoxia is a typical microenvironment feature in almost all solid tumors and is frequently associated with growth of cancers including colorectal cancer (CRC). This study focuses on the influence of hypoxic microenvironment on the activity of CRC cells and the molecules involved. CRC cells were cultured under hypoxic conditions for 48 h, after which the proliferation, migration, invasion, and epithelial-mesenchymal transition activities of cells were increased. MicroRNA- (miR-) 19a was significantly upregulated in cells after hypoxia exposure according to a microarray analysis. STAT3 was confirmed as an upstream regulator of miR-19a which bound to the promoter region of miR-19a at the 96 bp/78 bp sites, and miR-19a bound to the PTEN mRNA to activate the PI3K/AKT signaling pathway. Hypoxia exposure induced STAT3 phosphorylation and PTEN knockdown in CRC cells. Silencing of STAT3 reduced the hypoxia-induced activity of CRC cells, whereas the malignant behaviors of cells were restored after miR-19a upregulation but blocked after PTEN overexpression. Similar results were reproduced in vivo where downregulation of STAT3 or overexpression of PTEN suppressed tumor growth and metastasis in nude mice. This study demonstrated that hypoxia augments activity and malignant behaviors of colorectal cancer cells through the STAT3/miR-19a/PTEN/PI3K/AKT axis.
Highlights
Colorectal cancer (CRC) is a prevalent malignancy worldwide, and the mortality caused by it in China has exceeded the world average by 17%, which has not seen a significant decline in the past years [1]
It was found that the staining intensity of epithelial marker E-cadherin was decreased, whereas the intensity of the mesenchymal marker Vimentin was enhanced in cells exposed to hypoxic conditions (Figure 1(d))
These cellular experiments confirmed that hypoxia might regulate the cell microenvironment and stimulate activity of the CRC cells
Summary
Colorectal cancer (CRC) is a prevalent malignancy worldwide, and the mortality caused by it in China has exceeded the world average by 17%, which has not seen a significant decline in the past years [1]. One well-established characteristic of tumors is the rapid and uncontrolled proliferation, which limits the availability of oxygen, and hypoxia is a typical microenvironment feature in almost all solid tumors [3]. Limited oxygenation (hypoxia) is frequently associated with cancer growth and treating inefficacy [4]. Glycolysis maintains survival of cancer cells and enhances cell progresses, including proliferation, migration, and invasion [5]. An increased concentration of hypoxia-inducible transcription factors (HIFs) is usually involved, which is correlated with poor prognoses in many cancers, including CRC [6]. Identifying molecules involved in cancer progression, especially under hypoxic microenvironments, may help develop more ideas for CRC control
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