HES1-mediated down-regulation of miR-138 sustains NOTCH1 activation and promotes proliferation and invasion in renal cell carcinoma

Abstract

Background Although the aberrant activation of NOTCH1 pathway causes a malignant progression of renal cell carcinoma (RCC), the precise molecular mechanisms behind the potential action of pro-oncogenic NOTCH1/HES1 axis remain elusive. Here, we examined the role of tumor suppressive miR-138–2 in the regulation of NOTCH1-HES1-mediated promotion of RCC. Methods This study employed bioinformatics, xenotransplant mouse models, ChIP assay, luciferase reporter assay, functional experiments, real-time PCR and Western blot analysis to explore the mechanisms of miR-138–2 in the regulation of NOTCH1-HES1-mediated promotion of RCC, and further explored miR-138–2-containing combination treatment strategies. Results There existed a positive correlation between down-regulation of miR-138 and the aberrant augmentation of NOTCH1/HES1 regulatory axis. Mechanistically, HES1 directly bound to miR-138–2 promoter region and thereby attenuated the transcription of miR-138-5p as well as miR-138–2-3p. Further analysis revealed that miR-138-5p as well as miR-138–2-3p synergistically impairs pro-oncogenic NOTCH1 pathway through the direct targeting of APH1A, MAML1 and NOTCH1. Conclusions Collectively, our current study strongly suggests that miR-138–2 acts as a novel epigenetic regulator of pro-oncogenic NOTCH1 pathway, and that the potential feedback regulatory loop composed of HES1, miR-138–2 and NOTCH1 contributes to the malignant development of RCC. From the clinical point of view, this feedback regulatory loop might be a promising therapeutic target to treat the patients with RCC.

Sodium tanshinone IIA sulfonate inhibits tumor growth via miR-138 upregulation in intermittent hypoxia-induced xenograft mice

“…Our previous study [6] addressed the effects of TSA on tumor biological behaviors under the IH environment, these results demonstrated that TSA attenuated IHmediated oxidative stress and promoted apoptosis of tumor cells. In the current study, we confirmed that TSA exerts anti-tumor effects by inhibiting tumor Emerging studies [8,[26][27][28][29] have confirmed that miR-138 functions as a tumor suppressor by targeting several target genes associated with tumor proliferation, migration, invasion, and apoptosis. Under hypoxic conditions, miR-138 can serves as a tumor suppressor miRNA and is associated with hypoxia-induced factors [30].…”

Notch signaling pathway in cancer: from mechanistic insights to targeted therapies

“… 210 Functionally, HES1-mediated down-regulation of microRNA miR-138 maintains the activation of the Notch1 pathway and facilitates the malignant progression of RCC. 211 Consistently, selective Notch1 suppression by small interfering RNA could inhibit RCC cell proliferation via the JNK/p38 pathway. 212 Another study revealed that Notch3 was positively correlated with chromophobe RCC, unbroken capsule, Fuhrman grade 1, and less lymph node involvement.…”

Modulation of Notch Signaling by Small-Molecular Compounds and Its Potential in Anticancer Studies

“…Like IMR-1 and IMR-1A, SAHM1 attenuates Notch signaling by blocking the MAML/RPB-J interaction and its antitumor effects have been reported against bladder cancer [192] and acute myeloid leukemia [193]. However, SAHM1 showed no significant effects on B-cell acute lymphoblastic leukemia (B-ALL) In addition to DAPT, there are several extensively studied and tested GSI used to prevent NOTCH activation in cancer, including benzazepines such as Dibenzazepine (DBZ; YO-01027) [148][149][150], Crenigacestat (LY3039478) [151,152], LY411575 [153], and RO4929097 [154,155], sulfonamide derivatives such as Avagacestat (BMS-708163) [156,157], MK-0752 [158] and Venetoclax [159], or even natural compounds such as Hesperidin, a polyphenolic glycoside flavonoid that has shown anticancer potential in a colon cancer model [160]. In a broader sense, this further includes additional natural compounds such as Curcumin [161] or Evodiamine, an indole alkaloid that inhibits NOTCH3 signaling in a lung cancer model [162].…”