miR-486-3p Controls the Apoptosis of Endometrial Carcinoma Cells

Our study aimed to discuss the mechanism of miR-486-3p in controlling the apoptosis of endometrial carcinoma (EC) cells. EC cells were divided into NC group, miR-486-3p mimic and miR-486-3p inhibitor group followed by analysis of miR-486-3p level by Real-time PCR, cell proliferation by spectrophotometric method, apoptosis by FCM, cell migration and invasion by Transwell analysis. EC cells showed reduced miR-486-3p level. The EC malignant biological behaviors could be prompted through retraining miR-486-3p level with increased EC cell invasive capacity. DDR1 was a target of miR-486-3p. The variation of tumor activity could be regulated through controlling DDR1 expression. In conclusion, the apoptotic and invasive characteristic of EC cells are restrained after overexpression of miR-486-3p in EC cells through targeting DDR1, indicating that miR-486-3p could be considered to be one kind of brand-new target for the treatment of EC.

CircSEC24A upregulates TGFBR2 expression to accelerate pancreatic cancer proliferation and migration via sponging to miR-606

Background Circular RNA (circRNA), producing by special selective splicing, was widely expressed in the cytoplasm of eukaryotic cells as a newly non-coding RNAs. It played different roles in a variety of diseases including cancer and performed different functions. Nonetheless, reports on the specific function of circRNA in pancreatic cancer (PC) were still rarely so far. In particular, the role of circSEC24A in PC remains unclear. Methods Real-time fluorescent quantitative PCR was used to evaluate the expression level of circSEC24A in pancreatic cancer tissues and cell lines. Furthermore, we used some functional experiments, such as EDU and Transwell assays, to explore the effects of circSEC24A on the proliferation and invasiveness of pancreatic cancer. Finally, the corresponding relationship among circSEC24A, miR-606 and TGFBR2 was explored by dual luciferase reporter and other mechanism studies. Results The expression of circSEC24A in both pancreatic cancer tissues and cell lines was evidently up-regulated. Furthermore, knockdown of circSEC24A significantly inhibited the proliferative, migration and invasive capacity of pancreatic cancer cells, whereas miR-606 inhibitor obviously counteracted these effects. Further study confirmed that circSEC24A alleviated suppression on target TGFBR2 expression by directly sponging miR-606 and then influenced the tumorigenesis of pancreatic cancer. Conclusions These findings indicated that the progression of pancreatic cancer can be driven by circSEC24A influencing miR-606/TGFBR2 axis. Therefore, circSEC24A might be used as a critical biomarker influencing the early diagnosis and prognosis of pancreatic cancer.

The role, carrier and mission of neural crest cells in the skin

The neuro crest arising from the ectoderm is a transient structure and disappears as the neurocrest cells leave these places to invade the whole embryo. The epidermis develops from the ectoderm in the fourth embryonal weeks. The embryos consist of cranial-,vagal-, truncal and sacral segments and the neuro crest cells migrate from these places to form various structures, including the peripheral nerve system, the craniofacial bones and cartilages, etc. The neuro crest cells degrade the basal membrane of neural tube and thereafter migrate through the extracellular matrix in ventromedial and dorsolateral direction. Neural crest cells use various cell adhesion molecules and diferent proteaes. The invasive capacity of these cells is infuenced by aquaporin-1 , too. . The sensory nerves developig from the neuro- crest cells can be found in the epidermis and its appendicular organ, the dermal autonomic nerves in the dermis. The epidermal melanocytes develop partly from the neural crest cells, partly from the Schwann cells of the sensory nerves. The cutaneous nerves produce and secrete neuropeptides thus contributing to the development of the skin into a neuroimmuno-endocrin organ.

Mutant KRAS modulates colorectal cancer cells invasive response to fibroblast-secreted factors through the HGF/C-MET axis

Genetic alterations influence the malignant potential of cancer cells, and so does the tumor microenvironment. Herein, we combined the study of KRAS oncogenic effects in colorectal cancer cells with the influence of fibroblasts derived factors. Results revealed that mutant KRAS regulates cell fate through both autonomous and non autonomous signaling mechanisms. Specifically, processes such as proliferation and cell-cell aggregation were autonomously controlled by mutant KRAS independently of the stimulation with fibroblasts conditioned media. However, cancer cell invasion revealed to be a KRAS dependent non-autonomous effect, resulting from the cooperation between fibroblasts-derived HGF and mutant KRAS regulation of C-MET expression. C-MET downregulation upon KRAS silencing rendered cells less responsive to HGF and thus less invasive. Yet, in one cell line, KRAS inhibition triggered invasion upon stimulation with fibroblasts conditioned media. Inhibition of PIK3CA oncogene did not promoted invasion, thus showing a KRAS specific effect. Moreover, the invasive capacity also depended on the HGF-C-MET axis. Overall, our study awards oncogenic KRAS an important role in modulating the response to fibroblast-secreted factors either by promoting or impairing invasion, and depicts the HGF-C-MET axis as a putative therapeutic target to impair the invasive properties of mutant KRAS cancer cells.

TNF-α Regulated Endometrial Stroma Secretome Promotes Trophoblast Invasion

Successful implantation requires the coordinated migration and invasion of trophoblast cells from out of the blastocyst and into the endometrium. This process relies on signals produced by cells in the maternal endometrium. However, the relative contribution of stroma cells remains unclear. The study of human implantation has major technical limitations, therefore the need of in vitro models to elucidate the molecular mechanisms. Using a recently described 3D in vitro models we evaluated the interaction between trophoblasts and human endometrial stroma cells (hESC), we assessed the process of trophoblast migration and invasion in the presence of stroma derived factors. We demonstrate that hESC promotes trophoblast invasion through the generation of an inflammatory environment modulated by TNF-α. We also show the role of stromal derived IL-17 as a promoter of trophoblast migration through the induction of essential genes that confer invasive capacity to cells of the trophectoderm. In conclusion, we describe the characterization of a cellular inflammatory network that may be important for blastocyst implantation. Our findings provide a new insight into the complexity of the implantation process and reveal the importance of inflammation for embryo implantation.

SQSTM1/p62 in Intrahepatic Cholangiocarcinoma Promotes Tumor Progression Via Epithelial-Mesenchymal Transition and Mitochondrial Function Maintenance

Background: SQSTM1/p62, as a selective autophagy receptor, regulates multiple signaling pathways participating in the initiation and progression of tumors. Since metastasis is still a main cause for intrahepatic cholangiocarcinoma (ICC)-associated mortality, this study aimed to explore the mechanism of p62 promoting progression of ICC.Methods: Western blotting and immunohistochemical analysis were conducted to detect the expression level of protein p62 in ICC tissues. Subsequently, loss of function experiments was applied to define the role of p62 in the progression of ICC in vitro and in vivo. Mitochondrial function and mitophagy was evaluated by measuring oxygen consumption rates (OCR) and immunofluorescence detection respectively.Results: Here we identified expression of p62 was significantly upregulated in ICC specimens compared to normal tissue. And we further illustrated that p62 expression was positively correlated with lymph-node metastasis and poor prognosis. Loss of function assays revealed that p62 not only promoted ICC cells proliferation, migration and invasive capacity in vitro, but also induced lung metastasis in xenograft mouse model. Mechanistically, high expression of p62 induced epithelial-mesenchymal transition (EMT) with upregulation of Snail1, Vimentin and down-regulation of E-Cadherin. Moreover, OCR assays and immunofluorescence cell staining demonstrated that the autophagy-dependent function of p62 may play a vital role in maintaining mitochondrial function of ICC by mitophagy.Conclusions: These data provide new evidence and feasible mechanism that abundant p62 expression promote ICC progression, suggesting a promising therapeutic target for anti-metastatic strategies in ICC patients.

Identification of an Immune-Related LncRNA Signature in Gastric Cancer to Predict Survival and Response to Immune Checkpoint Inhibitors

Immune microenvironment in gastric cancer is closely associated with patient’s prognosis. Long non-coding RNAs (lncRNAs) are emerging as key regulators of immune responses. In this study, we aimed to construct a prognostic model based on immune-related lncRNAs (IRLs) to predict the overall survival and response to immune checkpoint inhibitors (ICIs) of gastric cancer (GC) patients. The IRL signature was constructed through a bioinformatics method, and its predictive capability was validated. A stratification analysis indicates that the IRL signature can distinguish different risk patients. A nomogram based on the IRL and other clinical variables efficiently predicted the overall survival of GC patients. The landscape of tumor microenvironment and mutation status partially explain this signature’s predictive capability. We found the level of cancer-associated fibroblasts, endothelial cells, M2 macrophages, and stroma cells was high in the high-risk group, while the number of CD8+ T cells and T follicular helper cells was high in the low-risk group. Immunophenoscore (IPS) is validated for ICI response, and the IRL signature low-risk group received higher IPS, representing a more immunogenic phenotype that was more inclined to respond to ICIs. In addition, we found RNF144A-AS1 was highly expressed in GC patients and promoted the proliferation, migration, and invasive capacity of GC cells. We concluded that the IRL signature represents a novel useful model for evaluating GC survival outcomes and could be implemented to optimize the selection of patients to receive ICI treatment.

circ-SIRT1 Promotes Colorectal Cancer Proliferation and EMT by Recruiting and Binding to eIF4A3

Circular RNA (circRNA), a recently identified type of endogenous noncoding RNA, has been implicated in the occurrence and development of a variety of tumors; however, whether circ-SIRT1, derived from pre-mRNA of the parental SIRT1 gene, is involved in colorectal cancer (CRC) remains unknown, as do the potential underlying mechanisms. The expression of circ-SIRT1 in CRC cells and tissue was detected by RT-qPCR. Colony formation and Cell Counting Kit-8 assays were used to evaluate the effect of circ-SIRT1 knockdown on the proliferative ability of CRC cells. Wound healing and Transwell assays were used to assess the effect of circ-SIRT1 knockdown on the migratory and invasive capacity of CRC cells. RNA immunoprecipitation and RNA pull-down assays were employed to validate the binding of circ-SIRT1 to EIF4A3. Western blot was used to identify the changes in the expression of EIF4A3 and EMT-related proteins. The RT-qPCR results showed that circ-SIRT1 was highly expressed in CRC cells and tissue and was positively correlated with the depth of tumor invasion. Knocking down circ-SIRT1 inhibited the proliferation and invasion of CRC cells and EMT. We further found that EIF4A3 could bind to circ-SIRT1, and that overexpressing circ-SIRT1 decreased the abundance of EIF4A3 at the mRNAs of the EMT marker proteins N-cadherin and vimentin. Combined, our findings suggested that circ-SIRT1 regulates the expression of EMT-related proteins by preventing EIF4A3 recruitment to the respective mRNAs. Our results further indicate that circ-SIRT1 functions as an oncogene in CRC by promoting the proliferation, invasion, and EMT of CRC cells through the circ-SIRT1/EIF4A3/N-cadherin/vimentin pathway.

The invasive pathogen Yersinia pestis disrupts host blood vasculature to spread and provoke hemorrhages

Yersinia pestis is a powerful pathogen with a rare invasive capacity. After a flea bite, the plague bacillus can reach the bloodstream in a matter of days giving way to invade the whole organism reaching all organs and provoking disseminated hemorrhages. However, the mechanisms used by this bacterium to cross and disrupt the endothelial vascular barrier remain poorly understood. In this study, an innovative model of in vivo infection was used to focus on the interaction between Y. pestis and its host vascular system. In the draining lymph nodes and in secondary organs, bacteria provoked the porosity and disruption of blood vessels. An in vitro model of endothelial barrier showed a role in this phenotype for the pYV/pCD1 plasmid that carries a Type Three Secretion System. This work supports that the pYV/pCD1 plasmid is responsible for the powerful tissue invasiveness capacity of the plague bacillus and the hemorrhagic features of plague.

Loss of miR-1469 expression mediates melanoma cell migration and invasion

Tumor ulceration is considered one of the most prognostically significant findings in primary cutaneous melanoma, associated with decreased disease-free and overall survival. However, the unique features associated with ulcerated melanoma that contribute to a poor prognosis in affected patients remain poorly defined. microRNAs are small, non-coding RNAs that function to inhibit expression of specific gene targets, therefore altering the functions of cells in which they are expressed. miR-1469 is a novel miR with significantly decreased expression in ulcerated melanoma tissue relative to non-ulcerated tumors. We hypothesized that loss of miR-1469 expression in melanoma contributes to altered tumor cell functions mediating disease progression. Transfection of a miR-1469 mimic resulted in a significant reduction in the migratory and invasive capacity of the CHL1 and MEL39 melanoma cell lines (>58.1% reduction, p < 0.0332), as well as the invasive capacity of the A375 melanoma cell line (>50% reduction, p < 0.0021). Expression of myeloid cell leukemia-1 (MCL1), a miR-1469 target gene, was reduced in the A375 and MEL39 cell lines by immunoblot. No significant differences in viability, resistance to apoptotic stimuli, or proliferation were observed following transfection. These findings together demonstrate how migration and invasion are specific functions through which miR-1469 expression in melanoma cells can contribute to the differences in disease progression associated with tumor ulceration.