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.
Highlights
Most, if not all, solid tumors are infiltrated with immune and inflammatory cells[1]
Analyzing the expression of miR-135b in Non-small-cell lung cancer (NSCLC) cell lines revealed that miR-135b was heterogeneously increased in 6/9 and dramatically upregulated over 30 folds in 5/9 of the analyzed cell lines compared with the normal BEAS-2B cell line (Fig. 1C)
Multivariate Cox analysis revealed that miR-135b was an independent prognostic factor for NSCLC with an HR of 4.822
Summary
If not all, solid tumors are infiltrated with immune and inflammatory cells[1]. Several cellular pathways have been proven to take part in cancer-related inflammation, among which the most prominent is the NF-κB pathway and interleukin 6 (IL-6)/ STAT3 signaling. Deubiquitinase that removes K63-linked poly-Ub from signaling intermediaries, such as CYLD and A20, had been proven to negatively regulate NF-κB signaling activation and tumor progression[11,12]. STAT3 signaling is hyperactivated in the majority of human cancers and a well-established intrinsic pathway driving inflammation, cellular transformation, survival, proliferation, invasion, angiogenesis, metastasis, and immune evasion in cancer[13,14]. IL-6 is a major cytokine activating STAT3 and is proposed to be related to advanced-stage disease and decreased survival in cancer[15]. NF-κB and STAT3 collaborate and engage in crosstalk in cancer Targeting these pathways has resulted in favorable oultcomes in cancer treatment[16,17]
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