Arsenite evokes IL-6 secretion, autocrine regulation of STAT3 signaling, and miR-21 expression, processes involved in the EMT and malignant transformation of human bronchial epithelial cells

Gong

Molecular Medicine Reports

et al. 2014

Abstract. The present study aimed to investigate the expression of interleukin-6 (IL-6) in gallbladder cancer (GBC) tissues and its correlation with survival rate. The association between IL-6 and epithelial-mesenchymal transition (EMT)-associated markers was also examined. Using immunohistochemistry, reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot analysis, the protein and mRNA expression levels of IL-6, Twist, E-cadherin and Vimentin in 20 GBC tissues were analyzed. The IL-6, Twist and Vimentin proteins were overexpressed in 40, 20 and 70% of the human GBC samples, respectively. The protein expression of E-cadherin was higher in only 5% of the GBC samples. These differences were significant (P<0.05). Western blot analysis also revealed overexpression of IL-6, Twist and Vimentin and underexpression of E-cadherin in the GBC samples with poor differentiation, local invasion and a higher tumor-node-metastasis (TNM) stage (P<0.05). Higher mRNA expression levels of IL-6, Twist and Vimentin and a reduced expression level of E-cadherin were also demonstrated in the GBC tissues (P<0.05). The degree of differentiation, local invasion, lymph node metastasis and clinical stage were significantly associated with the mRNA expression levels of IL-6, Twist and E-cadherin. The increased expression levels of IL-6 and Twist and the reduced expression of E-cadherin correlated with shorter median survival rates (P<0.05). Line regression results revealed correlation among the mRNA expression levels of IL-6, Twist, E-cadherin and Vimentin. To the best of our knowledge, the present study is the first to demonstrate that IL-6 is associated with EMT-associated markers, tumor differentiation, local invasion, TNM stage and survival rates in GBC.

Section: Discussionmentioning

confidence: 99%

Expression of interleukin-6 is associated with epithelial-mesenchymal transition and survival rates in gallbladder cancer

Gong

Molecular Medicine Reports

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

“…Immunostaining was performed as described previously [20]. Briefly, L-02 cells were stained with a rabbit antibody for Glut-4 at 4°C overnight and then incubated with Cy3-conjugated goat-anti-rabbit secondary antibody (Millipore, Billerica, MA) for 1 h. To stain the nuclei, 4′, 6-diamidino-2-phenylindole (DAPI, Sigma) was added for 10 min, and the cells were observed under a fluorescence microscope (Zeiss, LSM700B, Germany).…”

Section: Immunostainingmentioning

confidence: 99%

The lncRNA MALAT1, acting through HIF-1α stabilization, enhances arsenite-induced glycolysis in human hepatic L-02 cells

Luo

Liu

Ling

et al. 2016

Self Cite

Accelerated glycolysis, a common process in tumor cells called the Warburg effect, is associated with various biological phenomena. However, the role of glycolysis induced by arsenite, a well-established human carcinogen, is unknown. Long non-coding RNAs (lncRNAs) act as regulators in various cancers, but how lncRNAs regulate glucose metabolism remains largely unexplored. We have found that, in human hepatic epithelial (L-02) cells, arsenite increases lactate production; glucose consumption; and expression of glycolysis-related genes, including HK-2, Eno-1, and Glut-4. In L-02 cells exposed to arsenite, the lncRNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), and hypoxia inducible factors (HIFs)-α, the transcriptional regulators of cellular response to hypoxia, are over-expressed. In addition, HIF-1α, not HIF-2α, is involved in arsenite-induced glycolysis, and MALAT1 enhances arsenite-induced glycolysis. Although MALAT1 regulates HIF-α and promotes arsenite-induced glycolysis, MALAT1 promotes glycolysis through HIF-1α, not HIF-2α. Moreover, arsenite-increased MALAT1 enhances the disassociation of Von Hippel-Lindau (VHL) tumor suppressor from HIF-1α, alleviating VHL-mediated ubiquitination of HIF-1α, which causes accumulation of HIF-1α. In sum, these findings indicate that MALAT1, acting through HIF-1α stabilization, is a mediator that enhances glycolysis induced by arsenite. These results provide a link between the induction of lncRNAs and the glycolysis in cells exposed to arsenite, and thus establish a previously unknown mechanism for arsenite-induced hepatotoxicity.

“…TGF-β, the gold standard, has been used to efficiently induce EMT [4,22,23,24]. However, several stimuli can trigger EMT [25,26,27,28,29]. It is important to highlight that several of these stimuli, mainly cytokines and growth factors, activate signaling pathways and transcription factors as effectors, which can further modulate the activity and expression of splicing factors [30].…”

Section: Outside Stimuli Cause Cell Reprogramming and Changes In The mentioning

confidence: 99%

Aberrant Splicing in Cancer: Mediators of Malignant Progression through an Imperfect Splice Program Shift

Luz

Brígido²,

Moraes³

et al. 2016

Oncology

Although the efforts to understand the genetic basis of cancer allowed advances in diagnosis and therapy, little is known about other molecular bases. Splicing is a key event in gene expression, controlling the excision of introns decoded inside genes and being responsible for 80% of the proteome amplification through events of alternative splicing. Growing data from the last decade point to deregulation of splicing events as crucial in carcinogenesis and tumor progression. Several alterations in splicing events were observed in cancer, caused by either missexpression of or detrimental mutations in some splicing factors, and appear to be critical in carcinogenesis and key events during tumor progression. Notwithstanding, it is difficult to determine whether it is a cause or consequence of cancer and/or tumorigenesis. Most reviews focus on the generated isoforms of deregulated splicing pattern, while others mainly summarize deregulated splicing factors observed in cancer. In this review, events associated with carcinogenesis and tumor progression mainly, and epithelial-to-mesenchymal transition, which is also implicated in alternative splicing regulation, will be progressively discussed in the light of a new perspective, suggesting that splicing deregulation mediates cell reprogramming in tumor progression by an imperfect shift of the splice program.