MicroRNA-103a Curtails the Stemness of Non-Small Cell Lung Cancer Cells by Binding OTUB1 via the Hippo Signaling Pathway

Abstract

Objective: Although microRNA-103a (miR-103a) dysfunction has been implicated in various cancers, its relevance to non-small cell lung cancer (NSCLC) has not been clarified. This study was conducted to examine the molecular mechanism underlying the regulatory role of miR-103a in NSCLC. Methods: Kaplan–Meier analysis was carried out to assess the relationship between overall survival of NSCLC patients and miR-103a expression. Reverse-transcription quantitative polymerase chain reaction and western blot analyses were applied to evaluate the expression of relevant genes in tissues and cells. Sphere formation, MTS, flow cytometry, and Transwell assays were performed to characterize stemness. Dual luciferase reporter gene assays were used to clarify the binding relationship between miR-103a and ovarian tumor domain-containing ubiquitin aldehyde binding protein 1 (OTUB1). Finally, western blot analysis was used to assess the involvement of the Hippo pathway in NSCLC. Results: In NSCLC tissues and cells, miR-103a was expressed at low levels, whereas OTUB1 was expressed at high levels. Higher miR-103 expression levels were associated with a better prognosis for patients with NSCLC. When miR-103a was overexpressed, cell viability and stemness decreased, whereas apoptosis and cell cycle arrest were facilitated. The expression of phosphorylated YAP also decreased significantly. Opposite trends were observed after miR-103a silencing. OTUB1 expression and YAP phosphorylation decreased in the presence of miR-103a, and OTUB1 overexpression blocked the inhibitory effects of miR-103a on NSCLC cells. Conclusion: The miR-103a/OTUB1/Hippo axis may play a role in modulating the malignant behavior and stemness of cancer stem cells and thus could be a potential therapeutic target for the management of NSCLC.

Ubiquitin-specific peptidase 5 facilitates cancer stem cell-like properties in lung cancer by deubiquitinating β-catenin

“…Intriguingly, OTUB1 is reported to stabilize SLC7A11 through CD44, which is known to be an important CSC marker in human cancers [ 43 ]. Recently, another study also provided evidence showing that OTUB1 functions as an activator of the Hippo pathway to maintain CSCs in NSCLC [ 44 ]. Altogether, these data support our clinical findings, and we have identified a new role for USP5 in regulating stemness properties in lung cancer.…”

Involvement of the OTUB1‐YAP1 axis in driving malignant behaviors of head and neck squamous cell carcinoma

“…These findings suggest that OTUB1‐YAP1 axis may play an important role in HNSCC progression. It is noteworthy that the significance of both OTUB1 and YAP has been underscored in lung, gastric, and breast cancers 20,36,37 …”

“…It is noteworthy that the significance of both OTUB1 and YAP has been underscored in lung, gastric, and breast cancers. 20 , 36 , 37 …”

MicroRNA‑mediated regulation in lung adenocarcinoma: Signaling pathways and potential therapeutic implications (Review)

“…MiR-140-3p enhanced the sensitivity of LUAD cells to antitumor drugs by suppressing the Notch signaling pathway, and miR-182-5p plays a similar role through the Hedgehog pathway (136,139). Additionally, TGF β, Hippo, and YAP signaling pathways participated in the regulation of LUAD (142,158,160).…”