Dysregulation of the epidermal growth factor receptor (EGFR) promotes cancer cell growth, invasion and metastasis. However, its relevant downstream effectors are still limited. Here, we show that EGFR promotes breast tumor growth and metastasis by downregulating the tumor suppressor micoRNA-338-3p (miR-338-3p) and activating the EYA2 (EYA transcriptional coactivator and phosphatase 2) oncoprotein. EGFR represses miR-338-3p expression largely through HIF1α transcription factor. miR-338-3p inhibits EYA2 expression by binding to the 3′-untranslated region of EYA2. EGFR increases EYA2 expression via HIF1α repression of miR-338-3p. Through the miR-338-3p/EYA2 pathway, EGFR increases breast cancer cell growth, epithelial-to-mesenchymal transition, migration, invasion and lung metastasis in vitro and in a allograft tumor mouse model in vivo. In breast cancer patients, miR-338-3p expression negatively correlates with the expression of EGFR and EYA2, EGFR status positively associates with EYA2 expression, and miR-338-3p and EYA2 predict breast cancer lung metastasis when expressed in primary breast cancers. These data suggest that the miR-338-3p/ EYA2 axis contributes to EGFR-mediated tumor growth and lung metastasis and that miR-338-3p activation or EYA2 inhibition or combination therapy targeting EGFR/miR-338-3p/EYA2 axis may be a promising way to treat patients with metastatic cancer. Cell Death and Disease (2017) 8, e2928; doi:10.1038/cddis.2017.325; published online 13 July 2017The epidermal growth factor receptor (EGFR) is a member of the ErbB (avian erythroblastosis oncogene B) family of receptors and activates multiple signaling pathways, including mitogen-activated protein kinase (MAPK)/extracellular signalregulated kinases (ERK) and phosphoinositide-3-kinase (PI3K)/V-AKT murine thymoma viral oncogene homolog (AKT) pathways. 1-3 EGFR activation regulates many biological processes, such as cell proliferation, invasion, metastasis and apoptosis. [4][5][6] EGFR is overexpressed in various human cancers, including lung cancer, breast cancer, colon cancer and glioblastoma, and is associated with tumor malignancy and poor prognosis. 7-10 Thus, EGFR and its downstream signaling effectors have become targets for cancer therapy. 11 Approximately 90% of deaths associated with cancer are due to distant metastases. 12 Many cancers can metastasize anywhere in body but primarily metastasizes to some organs or tissues. For instance, lungs and bones are frequent sites of breast cancer metastasis. Although EGFR dysregulation enhances cancer metastasis, the relevant downstream effectors are largely unknown.MicroRNAs (miRNAs) are small noncoding RNA molecules (about 22 nucleotides in length), which function in RNA silencing and post-transcriptional regulation of gene expression. miRNAs participate in many biological processes, such as cell proliferation, invasion, metastasis, and apoptosis. 13 Recently, EGFR has been shown to promote prostate cancer bone metastasis by decreasing the expression of miR-1, a tumor suppressor, and inc...

ContextThyroid hormone influences glucose homeostasis through central and peripheral regulations. To date, the link between sensitivity to thyroid hormones and prediabetes remains unknown. We aimed to investigate the association between thyroid hormones sensitivity and risk of prediabetes in both general and euthyroid populations.MethodsParticipants with serum free triiodothyronine (FT3), free thyroxine (FT4), and thyrotropin (TSH) measurements from the health checkup programs of the First Hospital of China Medical University were collected. We measured the parameters representing central and peripheral sensitivities to thyroid hormones (central sensitivity, assessed by calculating Thyroid Feedback Quantile-based Index (TFQI), TSH Index (TSHI), and Thyrotroph Thyroxine Resistance Index (TT4RI); peripheral sensitivity, evaluated by FT3/FT4 ratio). Associations between thyroid hormones sensitivities and risk of prediabetes were assessed with logistic regression.ResultsA total of 4378 participants (mean age ± SD, 49 ± 11 years) were included, with 1457 (33%) subjects had prediabetes. The risk of prediabetes was negatively associated with levels of TSHI (odds ratio [OR] 0.91; 95% confidence interval [CI], 0.85–0.97), TT4RI (OR 0.91; 95% CI, 0.84–0.99) and Parametric TFQI (PTFQI) (OR 0.89; 95% CI, 0.83–0.95) among all subjects. The association remained significant in euthyroid subjects and euthyroid subjects with negative thyroid autoimmunity. Higher FT3/FT4 ratio was associated with a mild increased risk of prediabetes (95% CI 1.09; 1.02–1.16). Compared with subjects in the lowest quartile of PTFQI, those in the highest quartile had lower risk of prediabetes (0.70; 95% CI, 0.58–0.84).ConclusionsDecreased central sensitivity to thyroid hormones is associated with lower risk of prediabetes. This demonstrates the complex interaction between thyroid system and glucose metabolism. Future studies are warranted to confirm our findings and underlying mechanisms.

BCL-2 is a novel direct target of miR-30a-5p. miR-30a-5p enhances NSCLC paclitaxel sensitivity in vitro and in vivo. miR-30a-5p sensitizes NSCLC cells to paclitaxel by inducing apoptosis through BCL-2 inhibition. miR-30a-5p negatively correlates with BCL-2 and predicts a favorable clinical outcome in NSCLC patients.

Grave’s disease (GD) occurs due to an autoimmune dysfunction of thyroid gland cells, leading to manifestations consistent with hyperthyroidism. Various studies have confirmed the link between autoimmune conditions and changes in the composition of intestinal microbial organisms. However, few studies have assessed the relationship between the disease of GD and the changes of intestinal microbiota. Therefore, this study aimed to investigate changes in intestinal flora that may occur in the setting of GD. Thirty-nine patients with GD and 17 healthy controls were enrolled for fecal sample collection. 16S rRNA sequencing was used to analysis the diversity and composition of the intestinal microbiota. High-throughput sequencing of 16S rRNA genes of intestinal flora was performed on Illumina Hiseq2500 platform. Comparing to healthy individuals, the number of Bacilli, Lactobacillales, Prevotella, Megamonas and Veillonella strains were increased, whereas the number of Ruminococcus, Rikenellaceae and Alistipes strains were decreased among patients with GD. Furthermore, patients with GD showed a decrease in intestinal microbial diversity. Therefore, it indicates that the diversity of microbial strains is significantly deduced in GD patients, and patients with GD will undergo significant changes in intestinal microbiota, by comparing the intestinal flora of GD and healthy controls. Theses conclusion are expected to provide a preliminary reference for further researches on the interaction mechanism between intestinal flora and GD.

Aims The present study aims to determine the effects of sodium‐glucose cotransporter 2 (SGLT‐2) inhibitors on the serum uric acid (SUA) levels of patients with type 2 diabetes mellitus (T2DM) in Asia. Methods PubMed, CENTRAL, Embase and Cochrane Library databases were searched for randomized controlled trials of SGLT‐2 inhibitors in patients with T2DM up to 15 July 2021, without language or date restrictions. Results In total, 19 high‐quality studies (4218 participants) were included in the present network meta‐analysis. All of the included SGLT‐2 inhibitors (empagliflozin, dapagliflozin, canagliflozin, ipragliflozin, luseogliflozin and tofogliflozin) significantly decreased SUA levels compared with those of the control [total standard mean difference –0.965, 95% CI (−1.029, −0.901), p = .000, I2 = 98.7%] in patients with T2DM. Subgroup analysis and meta‐regression showed that the combined analysis of different inhibitors might lead to heterogeneity of the results. Therefore, among the SGLT‐2 inhibitors, the results of the subsequent network meta‐analysis revealed that luseogliflozin and dapagliflozin ranked the highest in terms of lowering SUA levels among the SGLT‐2 inhibitors. Moreover, the network meta‐analysis declared that luseogliflozin (1 and 10 mg) and dapagliflozin (5 mg) led to a superior reduction in SUA in patients with T2DM. Conclusions SGLT‐2 inhibitors could significantly reduce SUA levels in patients with T2DM, particularly luseogliflozin (1 and 10 mg) and dapagliflozin (5 mg) possess the best effects. Therefore, SGLT‐2 inhibitors look extremely promising as an antidiabetes treatment option in patients with T2DM with high SUA.