Reciprocal regulation of LINC00941 and SOX2 promotes progression of esophageal squamous cell carcinoma.

LINC00941 is a novel long noncoding RNA (lncRNA) and emerging as an important factor in cancer development. However, the exact function and relative regulatory mechanism of LINC00941 in carcinogenesis of esophageal squamous cell carcinoma (ESCC) remain to be further clarified. The present study was to investigate the expression level, functions, and mechanisms of LINC00941 in ESCC tumorigenesis. LINC00941 was significantly upregulated in ESCC, and upregulated LINC00941 was correlated with dismal patient outcomes. LINC00941 functioned as an oncogene by promoting cells proliferation, stemness, migration, and invasion in ESCC. In terms of mechanisms, SOX2 could bind directly to the promoter region of LINC00941 and activate its transcription. In turn, LINC00941 upregulated SOX2 through interacting with interleukin enhancer binding factor 2 (ILF2) and Y-box binding protein 1 (YBX1) at the transcriptional and post-transcriptional levels. LINC00941 recruited ILF2 and YBX1 to the promoter region of SOX2, leading to upregulation of the transcription of SOX2. Moreover, LINC00941 could promote the binding ability of ILF2 and YBX1 on mRNA of SOX2 and further stabilize SOX2 mRNA. Therefore, LINC00941 contributed to the malignant behaviors of ESCC cells via the unrestricted increase in SOX2 expression. In conclusion, our data indicate that LINC00941 exacerbates ESCC progression through forming a LINC00941-ILF2/YBX1-SOX2 positive feedback loop, and LINC00941 may be a promising prognostic and therapeutic target for ESCC.

FOXF2 deficiency accelerates the visceral metastasis of basal-like breast cancer by unrestrictedly increasing TGF-ß and miR-182-5p.

The mesenchymal transcription factor forkhead box F2 (FOXF2) is a critical regulator of embryogenesis and tissue homeostasis. Our previous studies demonstrated that FOXF2 is ectopically expressed in basal-like breast cancer (BLBC) cells and that FOXF2 deficiency promotes the epithelial-mesenchymal transition and aggressiveness of BLBC cells. In this study, we found that FOXF2 controls transforming growth factor-beta (TGF-ß)/SMAD signaling pathway activation through transrepression of TGF-ß-coding genes in BLBC cells. FOXF2-deficient BLBC cells adopt a myofibroblast-/cancer-associated fibroblast (CAF)-like phenotype, and tend to metastasize to visceral organs by increasing autocrine TGF-ß signaling and conferring aggressiveness to neighboring cells by increasing paracrine TGF-ß signaling. In turn, TGF-ß silences FOXF2 expression through upregulating miR-182-5p, a posttranscriptional regulator of FOXF2 and inducer of metastasis. In addition to mediating a reciprocal repression loop between FOXF2 and TGF-ß through direct transrepression by SMAD3, miR-182-5p forms a reciprocal repression loop with FOXF2 that directly transrepresses MIR182 expression. Therefore, FOXF2 deficiency accelerates the visceral metastasis of BLBC through unrestricted increases in autocrine and paracrine TGF-ß signaling, and miR-182-5p expression. Our findings provide novel mechanisms underlying the roles of TGF-ß, miR-182-5p, and FOXF2 in accelerating BLBC dissemination and metastasis, and may facilitate the development of therapeutic strategies for aggressive BLBC.

FOXF2 reprograms breast cancer cells into bone metastasis seeds.

Bone metastases occur in most advanced breast cancer patients and cause serious skeletal-related complications. The mechanisms by which bone metastasis seeds develop in primary tumors and specifically colonize the bone remain to be elucidated. Here, we show that forkhead box F2 (FOXF2) functions as a master transcription factor for reprogramming cancer cells into an osteomimetic phenotype by pleiotropic transactivation of the BMP4/SMAD1 signaling pathway and bone-related genes that are expressed at early stages of bone differentiation. The epithelial-to-osteomimicry transition regulated by FOXF2 confers a tendency on cancer cells to metastasize to bone which leads to osteolytic bone lesions. The BMP antagonist Noggin significantly inhibits FOXF2-driven osteolytic bone metastasis of breast cancer cells. Thus, targeting the FOXF2-BMP/SMAD axis might be a promising therapeutic strategy to manage bone metastasis. The role of FOXF2 in transactivating bone-related genes implies a biological function of FOXF2 in regulating bone development and remodeling.

Reciprocal transrepression between FOXF2 and FOXQ1 controls basal-like breast cancer aggressiveness.

FOXF2 and FOXQ1, forkhead box transcription factor superfamily members, are encoded by neighboring genes located on human chromosome 6p25.3 and play opposite roles in epithelial-mesenchymal transition (EMT) and metastasis in basal-like breast cancer (BLBC). However, the relationship between FOXF2 and FOXQ1 in cancer remains unknown. Here, we found mutual transcriptional repression between FOXF2 and FOXQ1, and the reciprocal negative feedback loop controlled EMT, aggressiveness, and chemoresistance in BLBC cells. We further demonstrated that FOXF2 recruited nuclear receptor corepressor 1 and histone deacetylase 3 to the FOXQ1 promoter to inhibit its transcription in BLBC cells, but FOXQ1 did not exert such an effect on FOXF2. Our findings reveal novel mechanisms underlying the determination of BLBC aggressiveness and the transrepressive function of FOXF2 in a basal-like cell subtype-specific manner. Therefore, blocking the vicious cycle of the abnormal reciprocal feedback loop between FOXF2 and FOXQ1 to induce cell differentiation and restore tissue homeostasis is a promising strategy for the treatment of aggressive BLBC.-Kang, L.-J., Yu, Z.-H., Cai, J., He, R., Lu, J.-T., Hou, C., Wang, Q.-S., Li, X.-Q., Zhang, R., Feng, Y.-M. Reciprocal transrepression between FOXF2 and FOXQ1 controls basal-like breast cancer aggressiveness.

Crosstalk between intestinal epithelial cell and adaptive immune cell in intestinal mucosal immunity.

Constantly challenged by luminal bacteria, intestinal epithelium forms both a physical and biochemical defense against pathogens. Besides, intestinal epithelium senses dynamic and continuous changes in luminal environment and transmits signals to subjacent immune cells accordingly. It has been long accepted that adaptive immune cells fulfill their roles partly by modulating function of intestinal epithelial cells. Recent studies have brought up the proposal that intestinal epithelial cells also actively participate in the regulation of adaptive immunity, especially CD4+ adaptive T cells, which indicates that there is reciprocal crosstalk between intestinal epithelial cells and adaptive immune cells, and the crosstalk may play important role in intestinal mucosal immunity. This Review makes a comprehensive summary about crosstalk between intestinal epithelial cells and CD4+ adaptive T cells in intestinal immunity. Special attention would be given to their implications in inflammatory bowel disease pathogenesis and potential therapeutic targets.

Handgrip Strength Index Predicts Nutritional Status as a Complement to Body Mass Index in Crohn's Disease.

BACKGROUND: Body mass index [BMI] is widely used to measure nutritional status in Crohn's disease [CD] patients, but limitations remain. Measuring handgrip strength index, in addition to BMI, may aid in overcoming limitations. METHODS: A total of 150 patients with CD and 254 controls were included in this study. All patients and controls underwent BMI, handgrip strength and bioelectrical impedance analysis. Bioelectrical impedance analysis included body cell mass, bone mineral content, skeletal muscle mass and body fat mass. A total of 88 CD patients were age-, sex- and BMI-matched with healthy controls for further analysis. RESULTS: BMI, body cell mass, body cell mass index, handgrip strength and handgrip strength index were all significantly decreased in the group of CD patients compared with controls [p < 0.0001]. When paired by BMI, healthy controls had significantly increased body cell mass index[p = 0.0344] and handgrip strength index [p = 0.0010] compared to patients. In addition, handgrip strength was well correlated with body cell mass [r = 0.8365, p < 0.0001]. CONCLUSIONS: BMI is widely used for detecting malnutrition, but it is less sensitive in predicting loss of body cell mass and skeletal muscle mass. Our study shows that handgrip strength index is an effective and convenient parameter to predict the functional nutritional status and muscular health in CD patients.

RUNX2 promotes breast cancer bone metastasis by increasing integrin α5-mediated colonization.

Runt-related transcription factor 2 (RUNX2) is regarded as an important contributor to breast cancer bone metastasis. However, previous studies did not provide direct clinical evidence for a role of RUNX2 in bone-specific metastasis in breast cancer, and the mechanism of RUNX2 in cancer cell recruitment and adhesion to the bone remains unclear. In this study, we showed that RUNX2 expression is positively correlated with the risk of bone-specific metastasis in lymph node-negative breast cancer patients. Then, we identified ITGA5 as a transcriptional target of RUNX2 from multiple candidate genes encoding adhesion molecules or chemokine receptors. We further provided experimental and clinical evidence that RUNX2, in an integrin α5-dependent manner, promotes the attraction and adhesion of breast cancer cells to the bone and confers cancer cell survival and bone colonization advantages. Overall, our findings clarify an adhesion-dependent mechanism of RUNX2 for the osteotropism and bone colonization of breast cancer cells and implicate RUNX2 and integrin α5 as potential molecular markers for the prediction of bone metastasis and therapeutic targets for the treatment of breast cancer bone metastasis.

Exosome in intestinal mucosal immunity.

Intercellular communication of immune cells is critical to elicit efficient inflammatory responses. In intestinal mucosa, imbalance in pro-inflammatory and anti-inflammatory mediators, especially cytokines and chemokines, characterizes the underlying immune mechanisms of inflammatory bowel disease. Exosomes, small membrane vesicles secreted into the extracellular environment, are emerging as another important intercellular messenger in immune responses. A major recent breakthrough in this field unveils the capacity of exosomes to mediate the functional transfer of genetic materials (mRNAs and miRNAs) between immune cells. RAB27A and RAB27B are two small GTPases involved in exosome secretion. With respect to intestinal mucosal immunity, increased number of RAB27A-positive immune cells and RAB27B-positive immune cells are demonstrated in the colonic mucosa of patients with active ulcerative colitis as compared with that of healthy controls. This indicates the important role of exosome-mediated immune responses in the pathogenesis of inflammatory bowel disease. Here, we will discuss the immune properties of exosomes and recent advances in their function with a special focus on intestinal mucosal immunity.

Proton diffusion determination and dual structure model for nickel hydroxide based on potential step measurements on single spherical beads.

Potential step measurement is carried out on single beads of spherical nickel hydroxide to determine the proton diffusion coefficient (D) and concentration of the effective proton vacancies (C). The semi-infinite diffusion equation for the initial stage and the finite diffusion equation for the long-term of the current response to potential step are used for deducing the D and C values. The diffusion coefficients deduced from short and long-term current responses are in the order of magnitude 10(-7) and 10(-10) cm2 s(-1), respectively. The sum of the effective proton vacancy concentrations associated with the two D values comes out to be equal within experimental error to the effective proton vacancy concentration converted from the released electricity during discharge. A dual structure model is proposed to interpret the above-mentioned findings, featuring densely packed grains within which proton diffusion is slow and an inter-grain matrix where proton diffusion is fast. With this model the huge difference (about 6 orders of magnitude) in D values reported in the literature as well as the controversy of the dependence of diffusion coefficient on the state of charge can be largely rationalized. This dual structure model is supported by SEM and AFM observations.