Emerging evidence has demonstrated that microRNAs (miRNA) play a critical role in chemotherapy-induced epithelial-mesenchymal transition (EMT) in breast cancer. However, the underlying mechanism of chemotherapy-mediated EMT has not been fully understood. To address this concern, we explored the role of miR-125b in regulation of EMT in stable paclitaxel-resistant (PR) breast cancer cells, namely MCF-7 PR and SKBR3 PR, which have displayed mesenchymal features. Our results illustrated that miR-125b was significantly downregulated in PR cells. Moreover, ectopic expression of miR-125b by its mimics reversed the phenotype of EMT in PR cells. Furthermore, we found that miR-125b governed PR-mediate EMT partly due to governing its target Sema4C. More importantly, overexpression of miR-125b or depletion of Sema4C sensitized PR cells to paclitaxel. These findings suggest that up-regulation of miR-125b or targeting Sema4C could serve as novel approaches to reverse chemotherapy resistance in breast cancers.
Gout is a multifaceted inflammatory disease involving vascular impairments induced by hyperuricemia. Experiments using human umbilical vein endothelial cells treated with uric acid (UA), monosodium urate (MSU), or serum from gout patients showed increased expression of pro-inflammatory genes (ie, VCAM1, ICAM1, CYR61, CCNA1, and E2F1) with attendant increase in monocyte adhesion. Mechanistically, UA-or MSU-induced SREBP2 expression and its transcriptional activity. RNA sequencing analysis and real-time PCR showed the induction of YAP signaling and pro-inflammatory pathways in HUVECs transfected with adenovirus-SREBP2. The How to cite this article: Zhao Z, Zhao Y, Zhang Y, et al. Gout-induced endothelial impairment: The role of SREBP2 transactivation of YAP.
The present study aimed to evaluate the correlation between the expression of microRNA-146a (miR-146a) and its target gene, LIN52, in advanced gastric cancer, and determine their potential effects on chemotherapeutic sensitivity and prognosis. Total RNA was extracted from 93 tissue samples of advanced gastric cancer and corresponding adjacent non-tumor tissues to quantify the relative expression levels of miR-146a using reverse transcription-quantitative polymerase chain reaction analysis. The expression of LIN52 was detected in tumors and normal tissues using immunohistochemical analysis. Correlation analysis was performed to assess the correlation between the expression of miR-146a and LIN52 and clinicopathological parameters of gastric cancer, including clinical diagnostic specificity, clinical tumor-necrosis-metastasis staging, lymph node metastasis, differentiation grade, chemotherapeutic sensitivity and prognosis. The expression of miR-146a in advanced gastric cancer tissues was lower, compared with that in the adjacent non-tumor tissues, and was negatively correlated with lymph node metastasis (P<0.05). Gastric cancer tissues with a low expression level of miR146a exhibited an increased expression level of LIN52 (P<0.05). Receiver operating characteristic curve regression analysis showed that miR-146a had 98% sensitivity in distinguishing gastric cancer tissues and adjacent non-tumor tissues. A high expression of miR-146a in gastric cancer was associated with improved treatment efficacy in patients. The chemotherapeutic sensitivity of patients with tumors expressing high levels of miR-146a was significantly higher, compared with that of patients with tumors expressing low levels of miR-146a (P<0.05). The expression of miR-146a was low in advanced gastric cancer tissues. As a tumor suppressor gene in advanced gastric cancer, miR-146a had a significant negative correlation with LIN52. High expression levels of miR-146a in advanced gastric cancer tissue may be associated with improved treatment efficacy of chemotherapy, suggesting that miR-146a may be a molecular marker for the diagnosis, prediction of treatment efficacy and prognosis of advanced gastric cancer.
BackgroundThe functions of the protein expressed in the nucleus and cytoplasm were different or opposite. The previous study found that oncogene Klf4 played a role of tumor suppressor in the nasopharyngeal cytoplasm. Cetuximab targeted epidermal growth factor receptor (EGFR) for the treatment of nasopharyngeal carcinoma.MethodsA cohort of 231 cases of advanced nasopharyngeal carcinoma (7th AJCC III–IVa) samples was assessed by immunohistochemistry (IHC), of which, 63 cases were treated with basic treatment without cetuximab, the basic treatment include chemotherapy and radiotherapy, the regent of the chemotherapy include cisplatin and fluorouracil and 168 cases were treated with cetuximab in addition to the basic treatment. The expression of the KLF4 protein was detected in nucleus and cytoplasm, c-Met protein and nuclear EGFR protein (nEGFR) by IHC, and H-Ras and PI3K mutations by an arms-PCR method in vivo. KLF4 was found to specifically express in the cytoplasm by deleting the NES, while H-Ras and PI3K genes were mutated in the nasopharyngeal carcinoma 5–8F and HONE1cell line. The cetuximab resistance in differentially mutated 5–8F and HONE1 cells was analyzed.ResultsThe expression of Klf4 in the nucleus was associated with prognosis in 168 patients with cetuximab-treated nasopharyngeal carcinoma, which was found by retrospective analysis. The KLF4 expression in the nucleus was not significantly correlated with the prognosis in 63 nasopharyngeal carcinoma patients treated with basic treatment (P = 0.261). The expression of Klf4 in the nucleus was correlated with mutations of H-Ras and PI3K in 168 cases of nasopharyngeal carcinoma with cetuximab treatment. In vitro experiments showed that Klf4 was specifically expressed in the nucleus of 5–8F and HONE1 cells as assessed by deleting nuclear export signal, which led to cetuximab resistance. H-Ras and PI3K mutations in 5–8F and HONE1 cells also led to the expression of Klf4 in the nucleus and resistance to cetuximab. In HONE1 cells, Klf4 was specifically localized in the cytoplasm by deleting the NES, and the H-Ras and PI3K mutations did not result in an increased expression of Klf4 in the nucleus and cetuximab resistance.ConclusionThe prognosis of nasopharyngeal carcinoma was not significantly improved by cetuximab treatment when the Klf4 was highly expressed in the nucleus of nasopharyngeal carcinoma tissues. The expression of Klf4 in the nucleus can be used as a biomarker for predicting the effects of cetuximab treatment in nasopharyngeal carcinoma, which might be attributed to the H-RAS and PI3K mutations, leading to cetuximab resistance.
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