Abstract
Hypoxia plays an essential role in orchestrating Epithelial-mesenchymal transition and promoting metastasis of colorectal cancer. However, the underlying mechanisms are still not well elucidated. Here, we present that hypoxic exposure causes endoplasmic reticulum stress and activates the unfolded protein response pathways, which drives GDF15 expression in colorectal cancer cells. Mechanistically, upregulated CHOP led by activated PERK-eIF2α signaling promotes GDF15 transcription via directly binding to its promoter. Further study implicates that hypoxia-induced GDF15 is required for the EMT and invasion of colorectal cancer cells; enforced expression of GDF15 promotes the mitochondrial oxidation of fatty acids in colorectal cancer cells. Moreover, the abrogation of GDF15 results in smaller xenograft tumors in size and impaired metastasis. GDF15 is expressed much more in tumor tissues of CRC patients and displays positive correlations with CHOP and HIF1α in mRNA levels. Our study demonstrates a novel molecular mechanism underlying hypoxia-promoted metastasis of CRC and provides PERK signaling-regulated GDF15 as a new and promising therapeutic target for clinical treatment and drug discovery.
Highlights
As one of the most malignant cancers, colorectal carcinoma (CRC) is the second most prevalent cause of death from cancer in the western world
Intriguing, the addition of tauroursodeoxycholic acid (TUDCA) almost abolished the impacts on epithelial-mesenchyme transition (EMT)-associated genes which were induced by hypoxia in HT29 cells (Figure 1(d)) and efficiently attenuated cell migration which was exacerbated by hypoxic exposure (Figures 1(e) and 1(f ))
To explore the physiological functions of upregulated Growth differentiation factor 15 (GDF15) in the setting of hypoxia, we investigated the role of GDF15 in tumor cell metastasis, which is highly promoted upon hypoxia. e ectopic expression of GDF15 in HT29 cells dramatically altered protein levels of EMT-associated genes expression, including increased N-cad and Vimentin while decreased E-cad (Figure 3(a))
Summary
As one of the most malignant cancers, colorectal carcinoma (CRC) is the second most prevalent cause of death from cancer in the western world. Hypoxic cells in a tumor mass accumulate free radicals resulted from shift cellular metabolism and stress the ER to accumulate misfolded proteins, which could activate the UPR pathways [19]. It is still uncertain whether hypoxic condition induces the activation of UPR in CRC cells. PERK-eIF2α branch is revealed as critical signaling in regulating EMT of tumor cells [21] We present that ER stress is dramatically induced by hypoxia exposure and subsequently activated PERK-eIF2α signaling promotes the metastasis via regulating GDF15 expression in CRC cells
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