Circ_0030411 aggravates cisplatin-resistance in non-small cell lung cancer by serving as a miR-495-3p sponge to enhance CCND1 expression.

Circular RNAsplay important modulators in cisplatin (DDP) resistant non-small cell lung cancer (NSCLC). Herein, the role and mechanism of circ_0030411 in DDP-resistant NSCLC was explored. Circ_0030411, miR-495-3p, CCND1, PCNA, Bax, E-cadherin, and ki-67 expression were examined byqRT-PCR, western blot and IHC. DDP resistance, cell proliferation, apoptosis, and motility were assessed usingCCK, EdU flow cytometry, and transwell. Xenograft tumour model was established to explore the role of circ_0030411 in DDP-resistant NSCLC. Interaction between miR-495-3p and circ_0030411 or CCND1 wasverified via luciferase reporterand RIP. Circ_0030411 and CCND1 were increased in DDP-resistant NSCLC tissues and cells, andmiR-495-3p level was decreased. Circ_0030411 knockdown hindered cell growth, migration, invasion, in DDP-resistant NSCLC cells, and improved DDP sensitivityof NSCLC in vivo. Mechanistically, circ_0030411 acted as a sponge of miR-495-3p to affect CCND1expression. Circ_0030411 facilitated DDP resistance by regulating the miR-495-3p/CCND1 axis, highlighting a promising target for NSCLC patients.

CircKIF4A promotes non-small cell lung cancer proliferation and metastasis through MiR-1238/CLDN14 axis.

As the leading cause of cancer-related death worldwide, non-small-cell lung cancer (NSCLC) is still in need of improved therapeutic strategies. CircKIF4A has been found to be involved in the progression of multiple cancers while its role in NSCLC remains unclear. To investigate the functions of circKIF4A, we assessed the expression of circKIF4A in NSCLC cells and tissues and performed experiments to determine the detailed functions of circKIF4A in NSCLC, including migration and proliferation. We found CircKIF4A expressed more heavily in the cells and tissues of NSCLC patients, and functional studies showed that inhibition of circKIF4A reduced NSCLC cells metastasis and proliferation. Furthermore, we seek to identify the underlying regulatory effect of circKIF4A in NSCLC. Studies revealed that circKIF4A sponged miR-1238 to promote NSCLC progression by up-regulating claudin14 (CLDN14) expression. In conclusion, circKIF4A is a potential diagnostic and therapeutic target in the circKIF4A/miR-1238/CLDN14 axis that plays an important role in NSCLC progression.

A high level of lncFGD5-AS1 inhibits epithelial-to-Mesenchymal transition by regulating the miR-196a-5p/SMAD6/BMP axis in gastric Cancer.

BACKGROUND: Long non-coding RNA (lncRNA) was a vital factor in the progression and initiation of human cancers. This study found a new lncRNA, FGD5-AS1, which can inhibit EMT process, proliferation, and metastasis in vitro and in vivo. METHODS: qRT-PCR was employed to test the expression of lncFGD5-AS1 in 30 gastric cancer patients' cancer tissue and para-cancer tissue. Overexpressed lncFGD5-AS1 cells shown sharply decrease of proliferation, migration, and epithelial-mesenchymal transition (EMT). miR-196a-5p/SMAD6 was confirmed as downstream molecular mechanism of lncFGD5-AS1 by expression correlation analysis and mechanism experiments. In vivo study illustrated overexpression of lncFGD5-AS1 suppression tumor growth. RESULTS: LncFGD5-AS1 served as a ceRNA of miR-196a-5p to release its inhibition on SMAD6, a conventional inhibitor on the BMP pathway. Comparing with normal gastric cancer cells, FGD5-AS1 overexpressed group had fewer migration cells, lower cell viability, and lower EMT transformation rate. Meanwhile, xenografts nude mice injecting with overexpressed-FGD5-AS1 cells also shown smaller tumor weight and volume. CONCLUSION: In conclusion, this research supported the first evidence that FGD5-AS1 suppressed proliferation and metastasis in gastric cancer by regulating miR-196a-5p/SMAD6/BMP axis and suggested a potential therapeutic candidate for gastric cancer.

Oxidative stress activates NORAD expression by H3K27ac and promotes oxaliplatin resistance in gastric cancer by enhancing autophagy flux via targeting the miR-433-3p.

Oxaliplatin resistance undermines its curative effects on cancer and usually leads to local recurrence. The oxidative stress induced DNA damage repair response is an important mechanism for inducing oxaliplatin resistance by activating autophagy. ELISA is used to detect target genes expression. TMT-based quantitative proteomic analysis was used to investigate the potential mechanisms involved in NORAD interactions based on GO analysis. Transwell assays and apoptosis flow cytometry were used for biological function analysis. CCK-8 was used to calculate IC50 and resistance index (RI) values. Dual-luciferase reporter gene assay, RIP and ChIP assays, and RNA pull-down were used to detect the interaction. Autophagy flux was evaluated using electron microscope and western blotting. Oxidative stress was enhanced by oxaliplatin; and oxaliplatin resistance gastric cancer cell showed lower oxidative stress. TMT labeling showed that NORAD may regulate autophagy flux. NORAD was highly expressed in oxaliplatin-resistant tissues. In vitro experiments indicate that NORAD knockdown decreases the RI (Resistance Index). Oxaliplatin induces oxidative stress and upregulates the expression of NORAD. SGC-7901 shows enhanced oxidative stress than oxaliplatin-resistant cells (SGC-7901-R). NORAD, activated by H3K27ac and CREBBP, enhanced the autophagy flux in SGC-7901-R to suppress the oxidative stress. NORAD binds to miR-433-3p and thereby stabilize the ATG5- ATG12 complex. Our findings illustrate that NORAD, activated by the oxidative stress, can positively regulate ATG5 and ATG12 and enhance the autophagy flux by sponging miR-433-3p. NORAD may be a potential biomarker for predicting oxaliplatin resistance and mediating oxidative stress, and provides therapeutic targets for reversing oxaliplatin resistance.

LINC00461 Overexpression Can Induce Docetaxel Resistance in Breast Cancer by Interacting with miR-411-5p.

PURPOSE: Breast cancer (BC) is the most common malignant cancer in women worldwide. Recently, long non-coding RNAs (LncRNAs) have been reported to have essential roles in BC tumorigenesis. PATIENTS AND METHODS: Tumor and adjacent non-tumor tissue samples were collected from patients with BC (n = 168) for comparison of LncRNA and miRNA expression levels. Patient clinical, demographic, and molecular data were analyzed by univariate and multivariate methods to identify factors associated with patient survival, and a nomogram was generated using significant risk/protective factors. Further, analyses of LINC00461 and miR-411-5p expression and function were conducted in BC and normal breast epithelial cell lines, by quantitative RT-PCR, cell proliferation, wound-healing, RNA pull-down, RNA immunoprecipitation, and luciferase assays. Docetaxel (DTX)-resistant BC cell lines were also generated and used to assess the roles of LINC00461 and miR-411-5p in drug resistance. RESULTS: LINC00461 was up-regulated in BC tissues relative to adjacent non-tumor samples, and expression of LINC00461 was correlated with poor patient prognosis. LINC00461 knockdown could inhibit proliferation of BC cells in vitro. Further, LINC00461 expression was higher in DTX-resistant than in non-resistant BC cell lines. Our data support a role for LINC00461 as a competitive endogenous RNA sponge involved in regulation of miR-411-5p expression in BC. miR-411-5p was down-regulated in both BC tissues and cell lines, with levels negatively correlated with those of LINC00461. Moreover, miR-411-5p was down-regulated in DTX-resistant BC cell lines compared with non-resistant cell lines. CONCLUSION: In conclusion, LINC00461 promotes proliferation, migration, and DTX-resistance in BC by acting as a sponge for miR-411-5p. This process represents a potential therapeutic target for patients with BC.

miR-615-3p promotes proliferation and migration and inhibits apoptosis through its potential target CELF2 in gastric cancer.

Gastric cancer incidence is relatively higher in China than that in developed countries; however, molecular mechanisms considering the initiation and progression of gastric cancer are still unclear. For decades, numerous microRNAs have been found to regulate a wide range of biological functions in gastric cancer. However, the oncogenic function of miR-615-3p in gastric cancer has not been reported to date. With the help of gene and microRNA chips in 10 patients, we were able to screen differential expressed genes and microRNAs compared with normal gastric tissues. After that, online bioinformatics analysis tools were used to predict microRNAs' potential targets. As a result, miR-615-3p and its potential target, CELF2, were selected for further experiments. QRT-PCR and western blot results indicated the aberrant high expression of miR-615-3p and low expression of CELF2 in gastric cancer both in vivo and in vitro. Moreover, miR-615-3p expression correlated to T and M stage. Up regulation of miR-615-3p inhibited the apoptosis, promoted proliferation and migration and led to the down-regulation of CELF2. Meanwhile, down-regulation of miR-615-3p resulted in anti-tumor effects. Immunochemistry staining of CELF2 showed its association with T, N and M stage. In addition, overexpression of CELF2 could reverse miR-615-3p's oncogenic functions stated before. These findings indicate that miR-615-3p promotes gastric cancer proliferation and migration by suppressing CELF2 expression for the first time, providing clues for future clinical practices.

MYC overexpression with its prognostic and clinicopathological significance in breast cancer.

BACKGROUND: Proto-oncogene MYC has been indicated to promote progression of many cancers. However, prognostic and clinicopathological significance of MYC in breast cancer need further evaluation. METHODS: We searched EMBASE and PubMed databases to find useful studies. We analyzed relationships between high MYC expression and prognostic data/ clinicopathological features through hazard ratio (HR) and odds ratio (OR). Each statistical test was two-sided. RESULTS: There were 29 studies (36 cohorts) with 12621 patients enrolled in our study The MYC overexpression was associated with worse DFS/RFS (disease/relapse free survival) in 11 studies (16 cohorts) with 5390 patients, and OS (overall survival) of 7 studies (8 cohorts) with 2672 patients. Subgroup analysis according to ethnicity/technique/data source displayed that MYC overexpression was associated with poor DFS/RFS in FISH, other technique, all data source and Asian/Non-Asian subgroup, and worse OS in all subgroups. In addition, MYC overexpression was related to large tumor size, high histologic grade, lymph node metastasis, negative hormone receptors and positive Ki67 expression. CONCLUSIONS: Our results showed that MYC overexpression was associated with worse prognosis and high risk of breast cancer, especially in patients with negative hormone receptors, which highlighted the potential of MYC as a significant prognostic biomarker of breast cancer.

Prognostic role of pretreatment neutrophil to lymphocyte ratio in breast cancer patients: A meta-analysis.

BACKGROUND: Inflammation and cancer are closely related to each other. As a parameter that can reflect inflammation and host immune reaction, elevated blood neutrophil to lymphocyte ratio (NLR) has been confirmed to be correlated with poor prognosis in a variety of cancers. However, this remains controversial in breast cancer. Thus, we performed this updated meta-analysis to further clarify whether high NLR could be a predictor of survival in breast cancer patients. METHODS: We searched on PubMed Database and Cochrane Library. Overall survival (OS), disease-free survival (DFS), and cancer-specific survival were used as outcome events, and hazard ratio (HR) was chosen as the parameter to evaluate the correlation. RESULT: Eighteen eligible studies were involved in this meta-analysis. The synthesized analysis demonstrated that elevated NLR was associated with poor DFS [HR = 1.72, 95% confidence interval (95% CI) = 1.30-2.27], OS (HR = 1.87, 95% CI = 1.41-2.48), and cancer-specific survival (HR = 2.09, 95% CI = 1.04-4.21). The correlation was stronger in triple-negative breast cancer (TNBC) (OS: HR = 2.58, 95% CI = 1.63-4.06; DFS: HR = 3.51, 95% CI = 1.97-6.24). CONCLUSION: Higher NLR was correlated to poor prognosis of breast cancer patients. As a clinical parameter that we can easily obtain, NLR might be a potential predictor in patients' survival to assist with physicians' treatment decisions.

Expression of LPA2 is associated with poor prognosis in human breast cancer and regulates HIF-1α expression and breast cancer cell growth.

Breast cancer (BC) generally exhibits poor prognosis owing to its invasive and metastatic characteristics and is the leading cause of cancer-related deaths in women worldwide. Lysophosphatidic acid receptor 2 (LPA2) and hypoxia inducible factor-1α (HIF-1α) were found to be correlated with BC invasion and metastasis, respectively. However, the effect of LPA2 on BC in Chinese women has not yet been reported, nor have the overall survival and prognostic significance of LPA2 or its association with HIF-1α in BC. In the present study, we assessed the effect of LPA2 on HIF-1α expression, on overall survival and prognostic significance in BC in Chinese women, and on cell proliferation, migration and invasion in MCF-7 BC cells in vitro. The data showed that LPA2 and HIF-1α protein expression levels were higher in the BC tissue specimens and that LPA2 expression was significantly associated with menopausal status (postmenopausal), nodal metastasis and tumor-node-metastasis (TNM) stage, whereas HIF-1α expression was significantly associated with estrogen receptor status, nodal metastasis and TNM stage. Furthermore, LPA2 and HIF-1α expression were positively correlated (r=0.562; P<0.001). LPA2 and HIF-1α protein levels were associated with shorter overall patient survival according to univariate analysis (log-rank test; P<0.001), and nodal metastasis, TNM stage, LPA2 and HIF-1α expression were independent prognostic predictors in patients as determined by multivariate analysis (P<0.05). In vitro, the data suggested that LPA2 affected HIF-1α expression and LPA2 overexpression or knockdown resulted in increased or inhibited tumor cell proliferation, migration and invasion, respectively. In conclusion, our data demonstrated that LPA2 expression was associated with HIF-1α expression and that a high level of LPA2 was associated with shorter overall survival and was an independent prognostic predictor for BC in Chinese women. Furthermore, LPA2 showed the ability to regulate the cell proliferation, migration and invasion of BC cells.

High tumor-associated macrophages infiltration is associated with poor prognosis and may contribute to the phenomenon of epithelial-mesenchymal transition in gastric cancer.

BACKGROUND: Recent studies show that epithelial-mesenchymal transition (EMT) and tumor-associated macrophages (TAMs) contribute to the progression and poor prognosis of carcinoma through multiple mechanisms. Both inflammation and changing of epithelium have a close relationship with tumorigenesis of gastric cancer. However, the relevance between EMT and TAMs is still unclear in gastric cancer and needs more scientific research. This study is designed to explore the relationship between EMT and TAMs in gastric cancer. MATERIALS AND METHODS: Immunohistochemistry was used to detect the expression of EMT-related proteins and TAM markers in cancer tissues and normal gastric tissues. RESULTS: High levels of EMT and TAMs infiltration are related to aggressive features and independent prognostic factors in gastric cancer, respectively. In addition, expression of the two indicators is associated with expression of transforming growth factor-ß1 (TGF-ß1). Infiltration of TAMs is also associated with EMT-related marker in gastric cancer. CONCLUSION: Our results suggest that high levels of EMT and TAMs infiltration are related to aggressive features and independent prognostic factors in gastric cancer, respectively. A correlation was found between EMT- and TAM-related indicators, which may be associated with TGF-ß signaling pathway. The level of TAMs infiltration plays an important role in gastric cancer, the markers of which can be used as prognostic indicators.

Perichondrium mesenchymal stem cells inhibit the growth of breast cancer cells via the DKK-1/Wnt/ß-catenin signaling pathway.

In recent years, mesenchymal stem cells (MSCs), which possess the ability to specifically home to tumor sites, with the potential of multi-directional differentiation and low immunogenicity, have been reported to inhibit the growth of various types of tumors. In the present study, we isolated MSCs from the rib perichondrium (PMSCs). By comparing PMSCs with bone marrow­derived mesenchymal stem cells (BMSCs), we demonstrated that PMSCs present biological characteristics similar to those of BMSCs. Furthermore, we explored the effect and antitumor mechanism of PMSCs in rat SHZ-88 breast cancer cells. The growth, migration and invasion of the SHZ-88 cells were significantly inhibited, and the Wnt/ß-catenin pathway and its target genes were downregulated in the SHZ-88 cells by PMSC-conditioned medium. The expression level of dickkopf-1 (DKK-1) was higher in the PMSCs than that noted in the SHZ-88 cells. Neutralization of DKK-1 in the PMSC­conditioned medium attenuated the inhibitory effects of PMSCs on SHZ-88 cells. Therefore, PMSC-secreted DKK-1 is involved in the inhibition of SHZ-88 cell growth, migration and invasion, via the Wnt/ß­catenin signaling pathway. In addition, we demonstrated that PMSCs inhibited the growth of breast cancer in vivo and prolonged the survival time of tumor­bearing rats. PMSCs inhibited the growth of transplanted breast tumors through the Wnt/ß-catenin signaling pathway. In conclusion, our data confirmed that MSCs derived from the perichondrium present biological characteristics similar to those of BMSCs and inhibit the growth of breast cancer cells through the Wnt/ß-catenin signaling pathway in vitro and in vivo. DKK-1 secreted by PMSCs played a vital role in controlling the Wnt/ß-catenin signaling pathway in breast cancer.