The prognostic significance of DDIT4 in endometrial cancer

Article type: Research Article

Authors: Yoshikawa, Nobuhisa^{a; *} | Yoshida, Kosuke^a | Liu, Wenting^b | Matsukawa, Tetsuya^a | Hattori, Satomi^a | Yoshihara, Masato^a | Tamauchi, Satoshi^a | Ikeda, Yoshiki^a | Yokoi, Akira^a | Shimizu, Yusuke^a | Niimi, Kaoru^a | Kajiyama, Hiroaki^a

Affiliations: [a] Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan | [b] Bell Research Center, Department of Obstetrics and Gynecology Collaborative Research, Nagoya University Graduate School of Medicine, Nagoya, Japan

Correspondence: [*] Corresponding author: Nobuhisa Yoshikawa, Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Tsuruma-cho 65, Showa-ku, Nagoya 466-8550, Japan. Tel.: +81 52 744 2261; E-mail: n-yoshikawa@med.nagoya-u.ac.jp.

Abstract: BACKGROUND: Despite extensive research on endometrial cancer and tumor hypoxic microenvironment, there are no reports exploring the role of DDIT4 in endometrial cancer. OBJECTIVE: This study aimed to elucidate the significance of DDIT4, as a prognostic biomarker for endometrial cancer by immunohistochemical staining and statistical analysis. METHODS: Four endometrial cancer cells were cultured under normoxia and hypoxia, and the differentially expressed genes were examined using RNA-seq. Immunohistochemical staining for DDIT4 and HIF1A was performed in 86 patients with type II endometrial cancer treated at our hospital, and their correlation with other clinicopathological factors and the prognostic role was analyzed using statistical methods. RESULTS: The expression analysis of hypoxia-inducible genes using four types of endometrial cancer cells revealed that DDIT4 was among the 28 genes that were upregulated in all cells. Based on our results of immunohistochemistry of DDIT4 expression in endometrial cancer tissues, univariate and multivariate analyses based on COX regression analysis showed that high DDIT4 expression significantly correlated to favorable prognosis in both progression-free survival and overall survival. Limited to recurrent cases, metastasis to only lymph nodes was significantly related to high DDIT4 expression, whereas metastasis to other parenchymal organs was significantly dominant in patients with low DDIT4 expression. CONCLUSIONS: The expression of DDIT4 enables to predict survival and recurrence in type II endometrial cancer.

Keywords: Endometrial cancer, DDIT4, HIF1A, hypoxia, RNA-seq

DOI: 10.3233/CBM-220368

Journal: Cancer Biomarkers, vol. 37, no. 4, pp. 217-225, 2023