EGR1 regulates radiation-induced apoptosis in head and neck squamous cell carcinoma

Abstract

Abstract. The transcription factor, early growth response 1 (EGR1) belongs to the early growth response family. EGR1 regulates the transactivation of genes involved in growth inhibition and apoptosis by ionizing radiation. The aims of the present study were to evaluate the expression of EGR1, and its relationship to prognosis, in patients with advanced laryngeal and hypopharyngeal squamous cell carcinoma (LHSCC) receiving chemoradiation therapy, and to observe the effect of EGR1 on the apoptosis of head and neck squamous cell carcinoma (HNSCC) cells treated with ionizing radiation. Expression of the EGR1 protein in tissue samples from patients with LHSCC was detected by immunohistochemistry. A high expression of the EGR1 protein was observed in 37 (67.3%) of the 55 LHSCC tissue samples examined. A high EGR1 protein expression in patients with LHSCC who were treated with chemoradiation was significantly associated with improved larynx-preservation survival (p=0.04). The 5-year diseasespecific survival rate with larynx preservation was 59% in patients with a high EGR1 protein expression vs. 30% in those with a low EGR1 protein expression. In the human HNSCC cell line, PCI50, EGR1 mRNA expression was induced at 30-60 min, and EGR1 protein expression was induced at 60-120 min, after exposure to a 5 Gy dose of ionizing radiation. To evaluate the impact of EGR1 on radiation-induced apoptosis, we used small-interfering RNA to knock down endogenous EGR1 gene expression. Cleaved caspase 3, cleaved caspase 7, and cleaved PARP were decreased, while XIAP was increased, in EGR1-knockdown PCI50 cells compared to negative control PCI50 cells, at all observed post-irradiation time points. These findings suggested that EGR1 knockdown inhibits radiation-induced apoptosis. In conclusion, EGR1 may be associated with larynx-preservation survival, through the regulation of radiation-induced apoptosis in patients with LHSCC treated with chemoradiation. Although further investigations are required to support the present study, EGR1 serves as a favorable biomarker of radiosensitivity in the treatment of LHSCC.

Radiation Induced Apoptosis of Murine Bone Marrow Cells Is Independent of Early Growth Response 1 (EGR1)

“…An indication to such complexity as it pertains to EGR1 regulation and its downstream effects is highlighted by the fact that while it is thought to be a tumor suppressor in most malignancies, EGR1 seems to be surprisingly oncogenic in prostate cancer [25, 54, 55]. This observation parallels the evidence suggesting that it can be a positive [27–29, 33, 34, 47, 48, 50–53] or a negative [25, 28, 30, 41, 54–57] regulator of apoptosis in different systems. Instead, we found that EGR1 is neither a positive nor a negative regulator of radiation induced apoptosis in murine bone marrow cells.…”

“…Several studies have demonstrated that it is a tumor suppressor in several model systems, human malignancies included [29, 45–48]. Haploinsufficiency of EGR1 cooperates with other mutations in the development of murine myeloid neoplasms [19, 26, 49], suggesting it might play a significant role in malignant transformation of stem cells leading to t-MNs.…”

“…EGR1 regulates cell growth and apoptosis in part by regulating expression of p53 [25, 27, 33, 34, 47]. In normal murine fibroblasts, normal hippocampal neurons, melanoma cells, a variety of human tumor cell lines, gliobastoma, non-small cell lung cancer, breast carcinoma, skin cancer as well as head and neck cancer, EGR1 is either pro-apoptotic or suppresses growth [27–29, 33, 34, 47, 48, 50–53]. On the contrary, in pancreatic beta cells, glioma and colorectal cancer cells, prostate cancer, B-cell lymphoma and normal B cells EGR1 has anti-apoptotic or pro-proliferative role [25, 28, 30, 41, 54–57].…”

“…EGR1 has a proapoptotic function in murine intestine and embryonic fibroblasts owing to its ability to stabilize p53 protein [27, 28]. The proapoptotic effect of EGR1 has also been observed in patients with advanced laryngeal and hypopharyngeal squamous cell carcinoma (LHSCC) receiving chemoradiation therapy [29]. In these patients, high EGR1 expression significantly correlated with therapy response and survival rate.…”

ATF3-Dependent Regulation of EGR1 in vitro and in vivo

“…A recently published study about the role of ATF3 in colorectal cancer supported the dual role of ATF3 in cancer progression [16]. Similar to ATF3, EGR1 seems to be involved in radiation-induced apoptosis [7,17]. The prior study discussed EGR1 as a biomarker of radiosensitivity in the treatment of HNSCC.…”