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STAT3/miR-135b/NF-κB axis confers aggressiveness and unfavorable prognosis in non-small-cell lung cancer
Jinlin Zhao1, Xin Wang1, Zeyun Mi2
1Department of Radiation Oncology, Tianjin Medical University Cancer Institute & Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, 300060, Tianjin, China.
Abstract:
Non-small-cell lung cancer (NSCLC) is one of the most commonly diagnosed cancers worldwide but has limited effective therapies. Uncovering the underlying pathological and molecular changes, as well as mechanisms, will improve the treatment. Dysregulated microRNAs (miRNAs) have been proven to play important roles in the initiation and progression of various cancers, including NSCLC. In this manuscript, we identified microRNA-135b (miR-135b) as a tumor-promoting miRNA in NSCLC. We found that miR-135b was significantly upregulated and that its upregulation was associated with poor prognosis in NSCLC patients. miR-135b was an independent prognostic factor in NSCLC. Overexpressing miR-135b significantly promoted the aggressiveness of NSCLC, as evidenced by enhanced cell proliferation, migration, invasion, anti-apoptosis, and angiogenesis in vitro and in vivo, and knockdown of miR-135b had the opposite effects. Mechanistically, our results reveal that miR-135b directly targets the 3'-untranslated region (UTR) of the deubiquitinase CYLD, thereby modulating ubiquitination and activation of NF-κB signaling. Moreover, we found that interleukin-6 (IL-6)/STAT3 could elevate miR-135b levels and that STAT3 directly bound the promoter of miR-135b; thus, these findings highlight a new positive feedback loop of the IL-6/STAT3/miR-135b/NF-κB signaling in NSCLC and suggest that miR-135b could be a potential therapeutic target for NSCLC.
Insights
MicroRNA-135b (miR-135b) promotes non-small-cell lung cancer (NSCLC) aggressiveness by targeting CYLD and activating NF-κB signaling. This miR-135b upregulation offers a potential therapeutic target for NSCLC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Non-small-cell lung cancer (NSCLC) presents limited therapeutic options, necessitating research into its pathological and molecular mechanisms.
- MicroRNAs (miRNAs) are implicated in cancer development, including NSCLC, making them targets for investigation.
Purpose of the Study:
- To identify novel microRNAs involved in NSCLC progression.
- To elucidate the role and mechanism of microRNA-135b (miR-135b) in NSCLC.
Main Methods:
- Quantitative real-time PCR to measure miR-135b levels in NSCLC tissues.
- In vitro and in vivo assays to assess the impact of miR-135b overexpression and knockdown on NSCLC aggressiveness.
- Luciferase reporter assays and Western blotting to investigate the molecular targets and signaling pathways affected by miR-135b.
Main Results:
- miR-135b was significantly upregulated in NSCLC and correlated with poor patient prognosis, acting as an independent prognostic factor.
- Overexpression of miR-135b enhanced NSCLC cell proliferation, migration, invasion, anti-apoptosis, and angiogenesis, while knockdown yielded opposite effects.
- miR-135b directly targets the 3'-UTR of CYLD, modulating NF-κB signaling. The IL-6/STAT3 pathway upregulates miR-135b, forming a positive feedback loop.
Conclusions:
- miR-135b acts as a tumor promoter in NSCLC by regulating the CYLD/NF-κB axis.
- A positive feedback loop involving IL-6/STAT3/miR-135b/NF-κB signaling contributes to NSCLC progression.
- miR-135b represents a promising therapeutic target for NSCLC treatment.
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