Hypoxia Enhances Activity and Malignant Behaviors of Colorectal Cancer Cells through the STAT3/MicroRNA-19a/PTEN/PI3K/AKT Axis

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.

Interplay of miRNAs and lncRNAs in STAT3 signaling pathway in colorectal cancer progression

“…STAT3 transcription factor binds to a region 96 bp/78 bp upstream of miR-19a within its promoter, leading to the induced expression of this oncogenic miRNA. The overexpression of miR-19a was shown to downregulate PTEN mRNA expression, promote cell viability and EMT in CRC cells, and increase tumor growth and metastasis in nude mice models through STAT3/miR-19a/PTEN axis [ 94 ]. Moreover, STAT3 has been illustrated to induce the expression of miR-181b as an oncomiR in CRC cells.…”

Mechanisms of chemotherapeutic resistance and the application of targeted nanoparticles for enhanced chemotherapy in colorectal cancer

“…HIF is closely associated with chemoresistance by activating the β-catenin/Wnt signaling pathway maintaining tumor cell stemness [ 109 ]. Tang et al [ 110 ] revealed that a hypoxic culture environment promotes STAT3 phosphorylation in CRC cells and promotes tumor progression through PI3K/AKT pathway activation.…”

Expression level comparison of marker genes related to early embryonic development and tumor growth

“…These nine factors occupy important positions in the large regulatory network of the body (22)(23)(24)(25)(26)(27). Changing of their expression may lead to changes or even loss of control of the regulatory network (22,(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37). In addition, these factors are highly related to the development and growth, regulatory mechanisms and microenvironment maintenance of early embryos (4,6,17,30,(38)(39)(40)(41)(42).…”

“…In addition, these factors are highly related to the development and growth, regulatory mechanisms and microenvironment maintenance of early embryos (4,6,17,30,(38)(39)(40)(41)(42). MYC (29,31,43), MYB (26), BCL-2 (44)(45)(46), BNIP3 (47), p53 (27,48), PI3K (22,28), AKT (23,49) and mTOR (32,(50)(51)(52)(53) are regarded as proto-oncogenes that serve important roles in cell proliferation and differentiation, apoptosis, cell cycle regulation and metabolic processes. In previous studies of mouse embryonic development, high mRNA and protein expression levels of these proto-oncogenes were also detected in mouse embryos.…”