BackgroundRecent evidence reveals that the inflammatory microenvironment is associated with tumor migration, invasion, and metastasis. Tumor necrosis factor-α (TNF-α) play a vital role in regulation of the inflammatory process in tumor development. Nuclear factor-kappa B (NF-κB) is one of the key transcription factors which regulate processes in tumor promotion. The aim of this study was to explore the role of NF-κB on the invasion and migration of oral squamous cell carcinoma (OSCC).Material/MethodsThe IKKβ and p65 mRNA and protein levels were determined by quantitative RT-PCR and western blot. Wound scratch healing assays and transwell migration assays were used to evaluate the effect of TNF-α and BAY11-7082 on the migration of the OSCC cell lines (HN4, HN6, and CAL27).ResultsWe observed a significant increase of the expression level of IKKβ and p65 in OSCC cells from the experimental group at 24 h, 48 h, and 72 h after TNF-α stimulation. Invasion and metastasis of OSCC cells was obviously improved after the TNF-α stimulation. Invasion and metastasis ability of OSCC cells was inhibited in the suppression group, and no significant changes were observed in expression level of IKKβ and p65 after the use of BAY11-7082.ConclusionsOur results suggest that TNF-α enhances the invasion and metastasis ability of OSCC cells via the NF-κB signaling pathway.

Bladder cancer is one of the most common urological malignancy all over the world. Recently, long non-coding RNA (lncRNA) XIST has been identified as an oncogenic gene in several type of cancers. However, the expression level and functional role of XIST in bladder cancer remain largely unknown. In the present study, we found that XIST was significantly up-regulated in bladder cancer tissues and cell lines, and was correlated with poor prognosis of bladder cancer patients. Furthermore, XIST knockdown significantly inhibited bladder cancer cell growth and metastasis in vitro and tumor growth in vivo. We also demonstrated that XIST acted as a competing endogenous RNA for miR-139-5p and repression of miR-139-5p could restore the inhibitory effects on bladder cancer cells induced by XIST shRNA. In addition, we identified that Wnt1 was a direct target of miR-139-5p, and XIST played the oncogenic role in bladder cancer by activating the Wnt/β-catenin signaling pathway. Taken together, our study suggested that lncRNA XIST may serve as a prognostic biomarker and a potential therapeutic target for bladder cancer.

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Gastric cancer prognoses are persistently poor due to cancer's penchant to metastasize. As a crucial regulator of signal transducer and activator of transcription (STAT3) signaling, sirtuin 1's (SIRT1) function in gastric cancer has not been well understood. Here, we report upregulated expression of SIRT1 in tissues isolated from gastric cancer patients. However, we show that the depletion of SIRT1‐mediated enhanced cancer cell proliferation and metastasis, and resulted in the enrichment of phosphorylated STAT3, acetylated STAT3, and matrix metalloproteinase 13 (MMP‐13) in both in vivo and in vitro experiments. Additionally, we demonstrate that small interfering RNAs targeting the production of STAT3, AG490, and CL‐821983 in cancer cells depleted of SIRT1 reduce metastasis. Our findings indicate that MMP‐13 expression is associated with lymph node metastasis and poor survival outcomes in gastric cancer patients. In vivo models also showed that depleted SIRT1 promoted gastric cancer growth via the STAT3/MMP‐13 axis. In conclusion, SIRT1 depletion encourages gastric cancer progression through the activation of STAT3/MMP‐13 signaling, suggesting that SIRT1 may function as a tumor suppressor. We postulate that the upregulation of SIRT1 in gastric cancer patients may be the result of a feedback mechanism that aims to oppose the damaging effects of STAT3 signaling. As such, SIRT1 activators could potentially serve as preventive and therapeutic treatments for metastatic gastric cancer.

Inflammation is one of the major causes of intervertebral disc degeneration (IDD).Emerging evidence has revealed that increase in the levels of pro-inflammatory cytokines, such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α), can activate a variety of signaling pathways, eventually resulting in IDD. Here, we show that the two cullin family genes, CUL4A and CUL4B, but not other cullins, are specifically overexpressed in IDD samples compared with healthy controls, and the CUL4A and CUL4B levels are positively correlated with the severity of IDD. In vitro analyses in human osteoblast cells (hFOB1.19), nucleus pulposus cells (hNPCs), and annulus fibrosus cells (hAFCs) indicated that treatment with IL-6 and TNF-α can increase CUL4A and CUL4B levels. By performing a microRNA-based microarray analysis, we found a set of microRNAs (miRNAs) that were differentially expressed in IDD samples compared with samples from healthy controls. Of these miRNAs, miR-194-5p, was significantly downregulated in IDD samples and could bind to the three prime untranslated regions (3′-UTRs) of both CUL4A and CUL4B, thereby downregulating their expression. The in vitro overexpression or downregulation of miR-194-5p, with a miR-194-5p-mimic or with anti-miR-194-5p, can cause the repression or induction of both CUL4A and CUL4B, respectively. Interestingly, treatment with IL-6 and TNF-α inhibitors in primary hNPCs and hAFCs that were isolated from patients with IDD led to the downregulation of CUL4A and CUL4B. Together, these findings provide insight into how the inflammation-dependent downregulation of miR-194-5p contributes to the pathogenesis of IDD, which may aid in the development of new therapeutic approaches for IDD by directly targeting miR-194-5p or CUL4A and CUL4B. K E Y W O R D S CUL4A, CUL4B, inflammation, intervertebral disc degeneration (IDD), microRNA (miRNA), miR-194-5p Additional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Chen Z, Han Y, Deng C, et al. Inflammation-dependent downregulation of miR-194-5p contributes to human intervertebral disc degeneration by targeting CUL4A and CUL4B.