GRIM-19 represses the proliferation and invasion of cutaneous squamous cell carcinoma cells associated with downregulation of STAT3 signaling.

The gene associated with retinoid-interferon-induced mortality-19 (GRIM-19) has been identified as a tumor suppressor in many human cancers. However, little is known about the role of GRIM-19 in cutaneous squamous cell carcinoma (CSCC). Here, we aimed to investigate the potential function of GRIM-19 in CSCC and explore the underlying molecular mechanisms. We found that GRIM-19 protein and transcript levels were significantly decreased in CSCC cell lines. Overexpression of GRIM-19 suppressed the proliferation and invasion of CSCC cells, whereas knockdown of GRIM-19 promoted the proliferation and invasion of CSCC cells. Also, we found that overexpression of GRIM-19 inhibited the phosphorylation and transcription activity of the signal transducer and activator of transcription 3 (STAT3). Overexpression of GRIM-19 also suppressed the expression of STAT3 target genes, including cyclin D1, Bcl-2 and metal matrix proteinase 2. By contrast, knockdown of GRIM-19 showed the opposite effect. Moreover, suppression of STAT3 significantly attenuated the effect of GRIM-19 knockdown on induction of proliferation, invasion, and STAT3 target genes in CSCC cells. Taken together, our data show that GRIM-19 suppresses the proliferation and invasion of CSCC cells associated with downregulation of STAT3 signaling, suggesting a tumor suppressive role of GRIM-19 in CSCC. Our study suggests that decreased expression of GRIM-19 may contribute to the development and progression of CSCC and that GRIM-19 may serve as a potential therapeutic target for CSCC treatment.

Wu N ，Hui H ，Cui L ，Yang F ... -  《-》

MicroRNA-125b exerts antitumor functions in cutaneous squamous cell carcinoma by targeting the STAT3 pathway.

MicroRNA-125b (miR-125b) is downregulated in human cutaneous squamous cell carcinoma (CSCC). However, its function in CSCC has yet to be extensively explored. Here, we analyze the relationship between signal transducer and activator of transcription 3 (STAT3) and miR-125b in CSCC. Western blotting and quantitative RT-PCR were used to determine the expression of the miR-125b-STAT3 axis in human CSCC tissues and cell lines. The direct regulatory effect of miR-125b on STAT3 expression was assessed using a luciferase reporter gene assay and RNA immunoprecipitation assay. The MTT assay and flow cytometry were used to determine the role of the miR-125b-STAT3 axis in CSCC cell proliferation and apoptosis. MiR-125b expression levels were significantly lower in CSCC cell lines and tissues than in normal cell lines and tissues. STAT3 was identified as the direct target of miR-125b. Upregulation of miR-125b and downregulation of STAT3 suppressed cell proliferation and promoted cell apoptosis. Cyclin D1 and Bcl2 were identified as the downstream targets of the miR-125-STAT3 axis. Our findings indicate that miR-125b acts as a tumor suppressor in CSCC by targeting the STAT3 pathway. This observation increases our understanding of the molecular mechanisms of CSCC. Therapies aimed at activating miR-125b or inhibiting STAT3 signaling should be explored as potential treatments for CSCC.

Tian K ，Liu W ，Zhang J ，Fan X ，Liu J ，Zhao N ，Yao C ，Miao G ... -  《-》

p53-Regulated Long Noncoding RNA PRECSIT Promotes Progression of Cutaneous Squamous Cell Carcinoma via STAT3 Signaling.

Long noncoding RNAs (lncRNAs) have emerged as putative biomarkers and therapeutic targets in cancer. The role of lncRNA LINC00346 in cutaneous squamous carcinoma (cSCC) was examined. The expression of LINC00346 was up-regulated in cSCC cells compared with normal human epidermal keratinocytes. Elevated expression of LINC00346 was noted in tumor cells in cSCC tissue sections in vivo, as compared with cSCC in situ, and actinic keratosis by RNA in situ hybridization; and the expression in seborrheic keratosis and normal skin was very low. Immunohistochemical analysis of cSCC tissue sections and functional assays of cSCC cells in culture showed that LINC00346 expression is down-regulated by p53. Knockdown of LINC00346 inhibited invasion of cSCC cells in culture and suppressed growth of human cSCC xenografts in vivo. Knockdown of LINC00346 inhibited expression of activated STAT3 and resulted in down-regulation of the expression of matrix metalloproteinase (MMP)-1, MMP-3, MMP-10, and MMP-13. Based on these observations LINC00346 was named p53 regulated carcinoma-associated STAT3-activating long intergenic non-protein coding transcript (PRECSIT). These results identify PRECSIT as a new p53-regulated lncRNA, which promotes progression of cSCC via STAT3 signaling.

Piipponen M ，Nissinen L ，Riihilä P ，Farshchian M ，Kallajoki M ，Peltonen J ，Peltonen S ，Kähäri VM ... -  《-》

GRIM-19 repressed hypoxia-induced invasion and EMT of colorectal cancer by repressing autophagy through inactivation of STAT3/HIF-1α signaling axis.

Hypoxia leads to cancer progression and promotes the metastatic potential of cancer cells. Thereby, the aim of the present study was to investigate the detailed effects of gene associated with retinoid-interferon-induced mortality-19 (GRIM-19) in colorectal cancer (CRC) cell lines under hypoxia conditions and explore the potential molecular mechanisms. Here, we observed that GRIM-19 expression was downregulated in several CRC cell lines as well as in HCT116 and Caco-2 cells under a hypoxic microenvironment. Additionally, the introduction of GRIM-19 obviously suppressed cell invasive ability and epithelial-mesenchymal transition (EMT) through modulating EMT markers as reflected by the upregulation of E-cadherin along with the downregulation of vimentin and N-cadherin under hypoxic conditions. Moreover, the addition of GRIM-19 repressed hypoxia-induced autophagy through modulating autophagy associated proteins as reflected by the downregulation of LC3-II/LC3-I ratio and Beclin-1 expression, as well as the increased of p62 expression. Interestingly, overexpression of GRIM-19 markedly ameliorated the accumulation of HIF-1α triggered by hypoxia accompanied by an inhibition of vascular endothelial growth factor (VEGF) production and phospho-signal transducer and activator of transcription 3 (p-STAT3) expression. Further data demonstrated that GRIM-19 have a negative feedback effect on the expression of HIF-1α. Mechanistically, re-expression of HIF-1α completely reversed the inhibitory effects of GRIM-19 on hypoxia-induced invasion and EMT. Taken all data together, our findings established that GRIM-19 suppresses hypoxia-triggered invasion and EMT by inhibiting hypoxia-induced autophagy through inactivation HIF-1α/STAT3 signaling pathway, indicating that GRIM-19 may serve as a potential predictive factor and therapeutic target for CRC treatment.

Zhang J ，Chu D ，Kawamura T ，Tanaka K ，He S ... -  《-》

WW domain-containing E3 ubiquitin protein ligase 1 depletion evokes antitumor effect in cutaneous squamous cell carcinoma by inhibiting signal transducer and activator of transcription 3 signaling pathway.

Xia Y ，Chang X ，Lian S ，Zhu W ... -  《-》