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Increasing studies have indicated that circular RNAs (circRNAs) play pivotal roles in various cancers. Here, we aimed to explore the roles of circRNAs in breast cancer. We identified a novel circRNA circKDM4B (hsa_circ_0002926) by whole-transcriptome sequencing and validated this by Real-time quantitative polymerase chain reaction (RT-qPCR) and Sanger sequencing. It was significantly decreased in breast cancer tissues compared with adjacent non-tumor tissues. Furthermore, circKDM4B, which is mainly localized in the cytoplasm, was more resistant to actinomycin D or ribonuclease R than its linear transcript KDM4B. In addition, the overexpression of circKDM4B inhibited cell migration and invasion in vitro, while knockdown of circKDM4B induced the opposite effects. In vivo, circKDM4B suppressed tumor growth and metastasis. Additionally, circKDM4B inhibited migration and tube formation of human umbilical vein endothelial cells (HUVECs) in vitro and angiogenesis in vivo. Mechanically, circKDM4B sponged miR-675 to upregulate the expression of NEDD4-like E3 ubiquitin protein ligase (NEDD4L), which catalyzes ubiquitination of PI3KCA, thereby inhibiting PI3K/AKT and VEGFA secretion. Collectively, these findings uncovered the tumor-suppressor role of circKDM4B in breast cancer, especially in angiogenesis and tumor metastasis, indicating that circKDM4B could be a potential therapeutic target for breast cancer progression.

Breast cancer (BC) is the most common malignant tumor in women worldwide. Metastasis is the main cause of BC-related death. The specific mechanism underlying BC metastasis remains obscure. Recently, PRSS22 was discovered to be involved in tumor development, however, its detailed biological function and regulatory mechanism in BC are unclear. Here, we characterized that PRSS22 expression is upregulated in BC tissues compared with non-tumorous breast tissues. Dual luciferase assays, bioinformatics analyses and chromatin immunoprecipitation (ChIP) assays indicated that transcription factor E2F1 directly binds to the PRSS22 promoter region and activates its transcription. Functionally, upregulation of PRSS22 promoted invasion and metastasis of BC cells in vitro and in vivo, whereas knockdown of PRSS22 inhibited its function. Mechanistically, the combination of PRSS22 and ANXA1 protein in BC cells was first screened by protein mass spectrometry analysis, and then confirmed by co-immunoprecipitation (Co-IP) and western blot assays. Co-overexpression of PRSS22 and ANXA1 could promote BC cell migration and invasion. We further demonstrated that PRSS22 promotes the cleavage of ANXA1 and in turn generates an N-terminal peptide, which initiates the FPR2/ERK signaling axis to increase BC aggressiveness.

Gastrointestinal (GI) cancers are among the most common cancer types and leading causes of cancer-related deaths worldwide. There is a tremendous clinical need for effective early diagnosis for better healthcare of GI cancer patients. In this article, we provide a short overview of the recent advances in GI cancer diagnosis. In the first part, we discuss the applications of blood-based biomarkers, such as plasma circulating cell-free DNA, circulating tumor cells, extracellular vesicles, and circulating cell-free RNA, for cancer liquid biopsies. In the second part, we review the current trends of artificial intelligence (AI) for pathology image and tissue biopsy analysis for GI cancer, as well as deep learning-based approaches for purity assessment of tissue biopsies. We further provide our opinions on the future directions in blood-based and AI-enhanced approaches for GI cancer diagnosis, and we think that these fields will have more intensive integrations with clinical needs in the near future.

Background Accumulating evidence demonstrated that long noncoding RNAs (lncRNAs) played important regulatory roles in many cancer types. However, the role of lncRNAs in gastric cancer (GC) progression remains unclear. Methods RT-qPCR assay was performed to detect the expression of HNF1A-AS1 in gastric cancer tissues and the non-tumourous gastric mucosa. Overexpression and RNA interference approaches were used to investigate the effects of HNF1A-AS1 on GC cells. Insight into competitive endogenous RNA (ceRNA) mechanisms was gained via bioinformatics analysis, luciferase assays and an RNA-binding protein immunoprecipitation (RIP) assay, RNA-FISH co-localisation analysis combined with microRNA (miRNA)-pulldown assay. Results This study displayed that revealed expression of HNF1A-AS1 was associated with positive lymph node metastasis in GC. Moreover, HNF1A-AS1 significantly promoted gastric cancer invasion, metastasis, angiogenesis and lymphangiogenesis in vitro and in vivo. In addition, HNF1A-AS1 was demonstrated to function as a ceRNA for miR-30b-3p. HNF1A-AS1 abolished the function of the miRNA-30b-3p and resulted in the derepression of its target, PIK3CD, which is a core oncogene involved in the progression of GC. Conclusion This study demonstrated that HNF1A-AS1 worked as a ceRNA and promoted PI3K/AKT signalling pathway-mediated GC metastasis by sponging miR-30b-3p, offering novel insights of the metastasis mechanism in GC.

Long noncoding RNAs (lncRNAs) are dysregulated in different cancer types, and thus have emerged as important regulators of the initiation and progression of human cancers. However, the biological functions and the underlying mechanisms responsible for their functions in gastric cancer (GC) remain poorly understood. Here, by lncRNA microarray, we identified 1414 differentially expressed lncRNAs, among which THAP7-AS1 was significantly upregulated in GC tissues compared with non-tumorous gastric tissues. High expression of THAP7-AS1 was correlated with positive lymph node metastasis and poorer prognosis. SP1, a transcription factor, could bind directly to the THAP7-AS1 promoter region and activate its transcription. Moreover, the m(6)A modification of THAP7-AS1 by METTL3 enhanced its expression depending on the “reader” protein IGF2BP1-dependent pathway. THAP7-AS1 promoted GC cell progression. Mechanistically, THAP7-AS1 interacted with the 1-50 Amino Acid Region (nuclear localization signal) of CUL4B through its 1-442 nt Sequence, and it promoted interaction between nuclear localization signal (NLS) and importin α1, and improved the CUL4B protein entry into the nucleus, repressing miR-22-3p and miR-320a expression by CUL4B-catalyzed H2AK119ub1 and the EZH2-mediated H3K27me3, subsequently activating PI3K/AKT signaling pathway to promote GC progression. Moreover, LV-sh-THAP7-AS1 treatment could suppress GC growth, invasion and metastasis, indicating that THAP7-AS1 may act as a promising molecular target for GC therapies. Taken together, our results show that THAP7-AS1, transcriptionally activated by SP1 and then modified by METTL3-mediated m6A, exerts oncogenic functions, by promoting interaction between NLS and importin α1 and then improving the CUL4B protein entry into the nucleus to repress the transcription of miR-22-3p and miR-320a.

Background Breast cancer is the most common cause of cancer-related death in women worldwide. MicroRNA (miRNA) ectopic expression has been reported to be involved in the regulation of gene expression in breast cancer. We screened several differentially expressed miRNAs associated with breast cancer chemoresistance, growth, and metastasis using a miRNA microarray. Increased expression of miR-4472 has been associated with larger breast tumors and chemoresistance. However, the biologic function of miR-4472 and its molecular mechanisms in cancer progression have not yet been reported. Materials and Methods Real-time quantitative polymerase chain reaction was used to measure the expression of miR-4472 in breast cancer tissue and cell lines. The biologic functions of miR-4472 and its target gene were explored using Transwell, cell proliferation, and flow cytometry assays. Bioinformatics tools, dual-luciferase reporter assays, and Western blot were used to identify the target genes of miR-4472. Western blot was used to explain the participation of miR-4472 and target gene in epithelial-to-mesenchymal transition. Results miR-4472 was significantly upregulated in highly metastatic breast cancer tissues, and its expression was positively associated with larger tumor size and advanced pTNM stage. miR-4472 promoted breast cancer cell metastasis and growth. Repulsive guidance molecule A (RGMA) was a direct target gene of miR-4472. RGMA was identified as a suppressor in cancer metastasis. miR-4472 downregulated expression of RGMA and promoted epithelial-to-mesenchymal transition by suppressing E-cadherin and initiating vimentin, β-catenin, and Slug. Conclusions miR-4472 contributes to the progression of breast cancer by regulating RGMA expression and inducing epithelial-to-mesenchymal transition, indicating that miR-4472/RGMA might serve as a therapeutic target for breast cancer.

Background Gastric cancer is the second most common cause of cancer-related mortality; thus, the mechanisms underlying tumor metastasis and growth in gastric cancer need to be extensively explored. Methods Differentially expressed genes were examined in gastric cancer samples with lymph node metastasis (LNM) and without LNM using mRNA microarray and RT-qPCR. The effects of G antigen 7B (GAGE7B) on the metastasis, growth, and angiogenesis of gastric cancer were investigated in vitro and in vivo. GAGE7B protein expression was detected by immunohistochemical (IHC) analysis. Microarray, RT-qPCR, and western blot assays were performed to detect downstream target genes of GAGE7B. Dual-luciferase reporter and western blot assays were used to identify miRNAs that could negatively regulate GAGE7B. Results GAGE7B was significantly overexpressed in samples with LNM. High expression levels of GAGE7B were associated with advanced clinical stage and poor patient survival. GAGE7B dramatically enhanced the metastasis, growth, and angiogenesis ability of gastric cancer. GAGE7B was further demonstrated to promote the progression of gastric cancer by activating the p38δ/pMAPKAPK2/pHSP27 pathway. However, the GAGE7B-induced p38δ/pMAPKAPK2/pHSP27 pathway was inactivated by miR-30c, as the expression levels of both GAGE7B and p38δ were found to be directly suppressed by miR-30c. Intriguingly, GAGE7B was found to be a ceRNA for p38δ, as it activated the p38δ/pMAPKAPK2/pHSP27 pathway by competitively binding miR-30c. Conclusions GAGE7B may serve as a prognostic indicator in gastric cancer. GAGE7B significantly promotes gastric cancer progression by upregulating the p38δ/pMAPKAPK2/pHSP27 pathway, but it is negatively regulated by miR-30c. GAGE7B and miR-30c may be potential therapeutic targets in gastric cancer. Electronic supplementary material The online version of this article (10.1186/s13046-019-1125-z) contains supplementary material, which is available to authorized users.

MicroRNAs have been reported to play key roles in various human cancers, including gastric cancer. However, understanding of the expression of miR-100 and its regulatory mechanisms in human gastric cancer remains elusive. In this study, we reveal that miR-100 is downregulated in gastric cancer samples and gastric cancer cell lines. Furthermore, lower miR-100 expression was found in primary gastric cancer samples with lymphatic metastasis compared to those without lymphatic metastasis. Overexpression of miR-100 suppressed tumor growth in vivo and inhibited gastric cancer invasion and metastasis in vitro and in vivo. Furthermore, we demonstrated that miR-100 reduced gastric cancer aggressiveness by directly targeting ZBTB7A. Knockdown of ZBTB7A by siRNA disrupted gastric cancer progression by impairing tumor invasion and metastasis. High expression of ZBTB7A was significantly correlated with poorer prognosis in gastric cancer patients. Our results also showed that the transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα) could induce the expression of miR-100 by binding to the putative promoter region of miR-100. This study demonstrated that miR-100 could be induced by C/EBPα and may act as a tumor suppressor gene by inhibiting ZBTB7A.

The protocadherin 7 is a member of the protocadherin family that expressed aberrantly in many types of human cancers. However, its expression, function, and underlying mechanisms are little known in gastric cancer. In this study, we detected protocadherin 7 expression in gastric cancer tissues and non-tumorous gastric mucosa tissues by real-time quantitative polymerase chain reaction and immunohistochemistry. The association of protocadherin 7 expression with the clinicopathological characteristics and the prognosis was subsequently analyzed. MTS ((3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium)) and transwell assays were performed to assess the effect of protocadherin 7 on proliferation, migration, and invasion in gastric cancer cell lines. Moreover, real-time quantitative polymerase chain reaction and western blot were used to detect the expression of epithelial–mesenchymal transition markers. Protocadherin 7 expression was decreased gradiently from normal tissue to gastric cancer, especially in gastric cancer tissue with lymph node metastasis. Low expression of protocadherin 7 was significantly associated with Lauren’s classification ( p = 0.0005), lymph node metastases ( p = 0.0002), and tumor node metastasis stage ( p = 0.0221), as well as poor prognosis ( p 0.05). Additionally, our results demonstrated that E-cadherin expression was down-regulated in gastric cancer cells with protocadherin 7 depletion. Our data indicated that protocadherin 7 may play important roles in the invasion and metastasis of gastric cancer, and protocadherin 7 could suppress cell migration and invasion through E-cadherin inhibition. Protocadherin 7 can serve as a novel biomarker for diagnostic and prognosis in patients with gastric cancer.

Transmembrane protease serine 4 (TMPRSS4) is a novel type II transmembrane serine protease that is overexpressed in various types of human cancers and has an important function in cancer progression. However, there is a paucity of data available regarding the biological effects of TMPRSS4 on breast cancer (BC) cells and the underlying mechanisms. In this study, expression of TMPRSS4 in BC tissues was detected by immunohistochemistry. The relationship between TMPRSS4 expression and clinicopathological characteristics as well as prognosis was evaluated. The effects of TMPRSS4 on cell proliferation, migration and invasion were investigated in BC cell lines in vitro. Additionally, RT-qPCR and western blot analysis were used to determine the expressions of epithelial-mesenchymal transition (EMT) biomarkers and TMPRSS4 in BC cell lines. We found that TMPRSS4 was overexpressed in BC tissues and its expression level was closely correlated with tumor size, histological grade, lymph node metastasis, clinical stage as well as poor survival (all P

The role of advanced glycation end products (AGEs) and its C-terminal truncated receptor (soluble receptor for advanced glycation end products, sRAGE) in ST-segment elevation myocardial infarction (STEMI) patients with or without diabetes is unknown. We compared their levels in patients with and without STEMI, as well as with and without diabetes. A prospective observational study was performed between December 2014 and December 2015. Study group included STEMI patients with coronary artery disease; control group included patients without coronary artery disease. Levels of AGEs and sRAGE were tested on Days 0, 2, and 5 after STEMI. Levels of creatine kinase-MB (CK-MB), cardiac troponin I, and N-terminal pro-brain natriuretic peptide (NT-proBNP) were tested on Days 0, 1, 2, and 3. Patient's diabetic status was determined by medical history or oral glucose tolerance test. Compared to patients in the control group, STEMI patients showed elevated levels of AGEs and sRAGE. In the STEMI group, diabetic patients had higher levels of AGEs and sRAGE compared to nondiabetic patients. The level of AGEs correlated with peak level of CK-MB in the overall population of patients with STEMI and with peak level of NT-proBNP in diabetic patients with STEMI. Levels of AGEs and sRAGE were elevated after STEMI, especially among patients with diabetes. These markers could serve to indicate the severity of myocardial injury and cardiac insufficiency, and play a potential role in predicting the prognosis of patients with STEMI.

Background Several studies have indicated that chronic kidney disease is independently associated with the presence of left ventricular hypertrophy ( LVH ). However, little clinical data are currently available regarding the detailed correlation between LVH and renal function in elderly patients with non–end‐stage renal disease. Methods and Results A total of 300 in‐ and outpatients (more than 60 years of age, non‐end‐stage renal disease), 251 with LVH and 49 without LVH , seen at Beijing Friendship Hospital from January 2000 to December 2010 were included in this retrospective study. One observation period of 12 months was used to detect rapid kidney function decline. The evaluations of cardiac structure and function were performed via echocardiography. The multivariable logistic analysis showed patients with LVH had a much higher risk of rapid kidney function decline than those without LVH . Additionally, the baseline left ventricular mass index was 140 (125–160) g/m 2 in the non–chronic kidney disease group, 152 (130–175) g/m 2 in the mild chronic kidney disease group (estimated glomerular filtration rate (eGFR)≥60 ml/min/1.73 m 2 ), and 153 (133–183) g/m 2 in the severe chronic kidney disease group (eGFR2 ), with a significant difference ( P =0.009). Conclusions Our data demonstrate that a high rate of renal function decline contributes to pathological LVH in non–end‐stage renal disease elderly patients and that LVH is positively associated with renal function decline followed by an increased risk of rapid kidney function decline.

Recent evidences indicate that retinal muller cells exhibit retinal progenitor characteristics under certain condition in chick, rat and human. However, there is no report on nonhuman primate, a close relative to human. In this study, we first established a muller cell line of rhesus monkey expressing GS, vimentin, CRALBP, EGFR, barely GFAP, which resemble the expression profile of human muller cells, differ from that of rodent. Expression of pax6, nestin, sox2, otx2, six6, and six3 was detected after one week culture in neural stem cell medium. Further culture with retinoic acid induced some cells differentiate toward neuron. These results suggest that primate muller cell is capable of dedifferentiating to retinal progenitors, which may serve as a potential cell source for cell therapy to treat retinal degenerative diseases.

To study the use of traditional Chinese medicine (TCM) or both TCM and guideline-recommended Western medicine (WM) in Chinese patients with coronary heart disease (CHD).A cross-sectional nationwide survey of 2803 CHD outpatients was completed by collecting information, including general demographic data, disease history, and use of drugs (including TCM and WM).Of the 2712 CHD outpatients with complete drug treatment data, only 3.1% received TCM without any WM for CHD, 30.0% received both TCM and WM recommended by current CHD guidelines, and 66.9% received only WM. Patients with a longer history of CHD or with a history of stroke, were more likely to use TCM. However, 90.6% of CHD patients who used TCM also used certain WM. Furthermore, patients who used more types of TCM tended to use much less WM recommended by current guidelines.A substantial proportion of Chinese CHD outpatients use both TCM and WM for secondary prevention of CHD. It is important to assess the effect of combined TCM and WM on major clinical outcomes in Chinese CHD patients.