Oncogenic cAMP responsive element binding protein 1 is overexpressed upon loss of tumor suppressive miR-10b-5p and miR-363-3p in renal cancer

Abstract

Renal cell carcinoma (RCC) is the most common kidney cancer in adults and has a poor prognosis. cAMP responsive element binding protein 1 (CREB1) is a proto‑oncogenic transcription factor involved in malignancies of various organs. However, its functional role(s) have not yet been elucidated in RCC. We investigated the expression pattern, function and regulation of CREB1 in RCC. CREB1 was overexpressed in the RCC tissues and cell lines. Downregulation of CREB1 inhibited RCC tumorigenesis by affecting cell proliferation, migration and apoptosis. Multiple computational algorithms predicted that the 3'‑untranslated region (3'‑UTR) of human CREB1 mRNA is a target for miR‑10b‑5p and miR‑363‑3p. Luciferase reporter assay, qPCR and western blot analysis confirmed that miR‑10b‑5p and miR‑363‑3p bind directly to the 3'‑UTR of CREB1 mRNA and inhibit mRNA and protein expression of CREB1. qPCR data also revealed a significantly lower expression of miR‑10b‑5p and miR‑363‑3p in RCC tissues. Introduction of miR‑10b‑5p and miR‑363‑3p mimics led to suppressed expression of CREB1 and inhibited cell proliferation, migration and apoptosis reduction. Taken together, we propose that CREB1 is an oncogene in RCC and that upregulation of CREB1 by loss of tumor suppressive miR‑10b‑5p and miR‑363‑3p plays an important role in the tumorigenesis of RCC.

Urinary exosome-derived microRNAs reflecting the changes of renal function and histopathology in dogs

“…miR-10b is expressed in the kidneys of mice, dogs, and cats34. The role of miR-10b in KD is unknown, but a previous report suggested that upregulation of cAMP responsive element binding protein 1 by loss of miR-10b plays an important role in the tumorigenesis of renal cell carcinoma21. Furthermore, miR-10b is significantly downregulated in rejected allografts, and miR-10b inhibition in human endothelial cells recapitulated apoptosis, release of pro-inflammatory cytokines/chemokine, and chemotaxis of macrophages22.…”

CREB1 directly activates the transcription of ribonucleotide reductase small subunit M2 and promotes the aggressiveness of human colorectal cancer

“…Besides, high expression of CREB1 is associated with metastasis in gastric and breast cancer [25, 26], while knockdown of CREB1 could inhibit liver cancer cell migration [27]. Consistently, CREB1 has also been identified to be highly expressed in glioma tissues and promote cell growth by activating the expression of oncogenic microRNA-23a [28], and plays an important role in the tumorigenesis of renal cancer by loss of tumor suppressive miR-10b-5p and miR-363-3p [29]. However, CREB1 functions like a tumor suppressor in other cancer types.…”

miR-10b is a prognostic marker in clear cell renal cell carcinoma

“…It is specifically located on chromosome 2q31 within the HOXD cluster, between HOXD4 and HOXD8 genes, closer to HOXD4 15. Interestingly, it is reported to be an oncomir in some cancers such as breast cancer,16 gastric cancer,17 hepatocellular carcinoma, glioma18 and lung cancer,19 whereas in other cancers including RCC, miR-10b was reported to have a tumour suppressor role 20 21…”

“…In hepatocellular carcinoma, miR-10b regulates metastasis and invasion by targeting cell adhesion molecule (CADM) 25. On the other hand, overexpression of miR-10b was shown to inhibit cellular proliferation, migration and invasion in RCC cell lines,21 26 but the exact regulatory mechanisms are not fully understood. Another study reported that loss of miR-10b results in increased expression of the CREB1 oncogene in RCC 21…”