Abstract
The KDEL (Lys-Asp-Glu-Leu) receptors (KDELRs), proteins with seven transmembrane domains, are primarily responsible for endoplasmic reticulum (ER) homeostasis. Recent studies have found additional function of KDELRs in growth, cellular secretory traffic, immune response, and autophagy; however, its role in tumorigenesis is still poorly understood. Here, we showed that KDELR2 is highly expressed in glioblastoma (GBM) tissues. Reviewing the expression of KDELR2 in TCGA and REMBRANDT database, we found that higher expression of KDELR2 is associated with shorter survival of GBM patients. We explored the effect of KDELR2 on tumorigenesis in GBM cells and animal model (nude mice), and identified KDELR2 as oncogene promoting cell proliferation. Additionally, KDELR2 expression in GBM cells correlated positively with HIF1alpha (HIF1α) expression, and we demonstrated by ChIP-qPCR and luciferase reporter assay that the upstream region of the KDELR2 gene is directly targeted by HIF1alpha. Taken together, our data suggest that KDELR2 is a target gene downstream of HIF1-alpha driving the malignancy of GBM and could eventually serve as a therapeutic target for the treatment of GBM patients.
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This work was supported by National Natural Science Foundation of China [81702481], National Natural Science Foundation of Tianjin [15JCQNJC44800].
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CS and LM conceived the project and designed the study; ZL and CS performed most of the experiments; ZS and XZ assisted in some in vitro experiments; PL, PW, and WL provided clinical samples; LM provided reagents and conceptual advice; ZL and CS wrote the manuscript. All authors discussed the results and commented on the manuscript.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of Ethics Committee of Tianjin Medical University Cancer Institute & Hospital (China) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All procedures performed in studies involving animals were in accordance with the ethical standards of the Ethics Committee of Tianjin Medical University Cancer Institute & Hospital (China) or practice at which the studies were conducted.
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Liao, Z., She, C., Ma, L. et al. KDELR2 Promotes Glioblastoma Tumorigenesis Targeted by HIF1a via mTOR Signaling Pathway. Cell Mol Neurobiol 39, 1207–1215 (2019). https://doi.org/10.1007/s10571-019-00715-2
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DOI: https://doi.org/10.1007/s10571-019-00715-2