Abstract
Renal cell carcinoma (RCC) is a frequent malignancy of the urinary system. It has been found that hypoxia mediates the malignant evolvement of RCC. Here, we probe the impact and potential mechanism of HECT domain E3 ubiquitin-protein ligase 2 (HECTD2) and HIF-1α on regulating RCC evolvement. RCC tissues and adjacent normal tissues were collected, and the association between the expression profiles of HECTD2 and HIF-1α and the clinicopathological features was analyzed. Additionally, we constructed HECTD2/HIF-1α overexpression and knockdown models in RCC cell lines to ascertain the impacts of HECTD2 and HIF-1α on RCC cell proliferation, apoptosis, migration, and growth in vivo. We applied bioinformatics to predict the upstream miRNA targets of HECTD2. Meanwhile, RNA immunoprecipitation (RIP), and the dual-luciferase reporter assays were employed to clarify the targeting association between HECTD2 and miR-320a. The effect of miR-320a on HECTD2-mediated RCC progression was investigated. The results suggested that both HIF-1α and HECTD2 were up-regulated in RCC (compared with adjacent non-tumor tissues), and they had positive relationship. Moreover, higher level of HECTD2 and HIF-1α is associated with poorer overall survival of RCC patients. HECTD2 overexpression heightened RCC cell proliferation and migration, and weakened cell apoptosis. On the other hand, the malignant phenotypes of RCC cells were signally impeded by HECTD2 or HIF-1α knockdown. Moreover, miR-320a targeted the 3′-untranslated region of HECTD2 and suppressed HECTD2 expression. The rescue experiments showed that miR-320a restrained HECTD2-mediated malignant progression in RCC, while up-regulation of HIF-1α hampered miR-320a expression. Collectively, HIF-1α mediated HECTD2 up-regulation and aggravated RCC progression by attenuating miR-320a.
Highlights
Renal cell cancer (RCC) is the third most familiar genitourinary malignancy globally, with a high mortality rate (Shingarev and Jaimes, 2017)
To investigate whether Hypoxia-inducible factor 1α (HIF-1α) and HECTD2 contribute to RCC progression, we consulted the database and discovered that HIF-1α and HECTD2 levels were both highly expressed in RCC tissues (Figures 1A,B)
WB results uncovered that HIF-1α and HECTD2 expression levels were significantly higher in tumor tissues of RCC patients than those in corresponding surrounding non-tumor tissues (Figures 1C,D)
Summary
Renal cell cancer (RCC) is the third most familiar genitourinary malignancy globally, with a high mortality rate (Shingarev and Jaimes, 2017). It has been revealed that miR-340 is up-regulated in RCC, which accelerates RCC cell proliferation, migration and invasion by hampering the FZD3 profile (Xiang et al, 2021). MiR-31-5p is lowly expressed in RCC, and it attenuates the malignant behaviors of RCC cells by targeting and reversely modulating HMGA1 (Liu et al, 2021). Cheng C et al have found that miR-26a-5p is knocked down in RCC, and it curbs RCC cell proliferation and invasion and intensifies cell death by targeting E2F7 (Cheng et al, 2020). Cheng C et al have found that miR-26a-5p is knocked down in RCC, and it curbs RCC cell proliferation and invasion and intensifies cell death by targeting E2F7 (Cheng et al, 2020). miR320a has been found sponged by lncRNA CCAT2 (Wu et al, 2020), but its downstream mechanism in RCC progression needs further investigation
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