HIF1α inhibitor 2-methoxyestradiol decreases NRN1 expression and represses in vivo and in vitro growth of patient-derived testicular germ cell tumor spheroids
| Autor: | Takashi Suzuki, Akihiro Yano, Satoru Kawakami, Sachi Kitayama, Koji Okamoto, Kuniko Horie-Inoue, Takeshi Namekawa, Kazuhiro Ikeda, Tomohiko Ichikawa, Satoshi Inoue |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Cancer Research Small interfering RNA Testicular Germ Cell Tumor Antineoplastic Agents Biology GPI-Linked Proteins 03 medical and health sciences 0302 clinical medicine Testicular Neoplasms In vivo Cell Line Tumor Spheroids Cellular medicine Humans 2-Methoxyestradiol Cell Proliferation Gene knockdown Neuropeptides hemic and immune systems Neoplasms Germ Cell and Embryonal Hypoxia-Inducible Factor 1 alpha Subunit Xenograft Model Antitumor Assays In vitro 030104 developmental biology HIF1A Oncology Hypoxia-inducible factors 030220 oncology & carcinogenesis Cancer research medicine.drug |
| Zdroj: | Cancer letters. 489 |
| ISSN: | 1872-7980 |
| Popis: | Testicular germ cell tumor (GCT) is the most common type of malignancy in young males. Patients with nonseminomatous GCT still have poor prognosis. To identify new therapeutic targets, we generated patient-derived cells (PDCs) and their xenograft (PDCX) models from 3 distinct GCT patients' specimens. The pathological features of GCT PDCs and PDCX tumors recapitulated those of nonseminomatous components exhibiting in the corresponding patients' specimens. Notably, stemness-related markers and hypoxia-related genes, including hypoxia inducible factor 1α (HIF1A) and neuritin 1 (NRN1), were abundantly expressed in three-dimensional spheroid cultures of GCT PDCs. We identified functional HIF1α response elements in the NRN1 promoter and defined that their transcriptional activities were substantially activated by hypoxia. HIF1α inhibition by siRNAs or an inhibitor, 2-methoxyestradiol, significantly suppressed NRN1 expression and decreased the in vitro and in vivo growth of PDC spheroids. Moreover, NRN1 knockdown efficiently suppressed PDC proliferation. These results suggest that HIF1α and NRN1 are potential diagnostic and therapeutic targets, and that 2-methoxyestradiol could be applied to clinical management of GCT. Overall, our GCT PDC and PDCX models would be useful as preclinical models for precision medicine targeting each patient. |
| Databáze: | OpenAIRE |
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