LncRNA DLX6-AS1 regulates osteosarcoma progression via the miR-200a-3p/GPM6P axis

LncRNA DLX6-AS1 takes part in the progression of various cancers. However, it is not elaborated clearly in osteosarcoma (OS) development. Therefore, we aimed to explore the impacts and specific mechanisms of DLX6-AS1 on the progression of OS. We estimated the pattern of DLX6-AS1 expression in Ost tissues and cells via quantitative reverse transcription polymerase chain reaction. A number of biochemical assays were carried out to assess the effects of DLX6-AS1. Target genes were predicted by bioinformatics methods. Then we used the transfection of si-RNA, miRNA inhibitor, and miRNA mimics to explore the underlying mechanisms and built tumor xenograft models for the in vivo experiments. A higher expression of DLX6-AS1 was found in OS tissues and cell lines, while knockdown of DXL6-AS1 suppressed OS cell metastasis and proliferation in vitro and in vivo. Mechanistically, it was revealed that DXL6-AS1 sponged miR-200a-3p, thus positively regulating the downstream GPM6B. In summary, DLX6-AS1 knockdown would inhibit OS cell migration, cell invasion, and cell proliferation, in which the DXL6-AS1/ miR-200a-3p/ GPM6B axis played a critical role.

Small extracellular vesicles: from mediating cancer cell metastasis to therapeutic value in pancreatic cancer

Pancreatic cancer is a highly malignant tumor and, is extremely difficult to diagnose and treat. Metastasis is one of the critical steps in the development of cancer and uses cell to cell communication to mediate changes in the microenvironment. Small extracellular vesicles (sEVs)-carry proteins, nucleic acids and other bioactive substances, and are important medium for communication between cells. There are two primary steps in sVEs-mediated metastasis: communication between pancreatic cancer cells and their surrounding microenvironment; and the communication between primary tumor cells and distant organ cells in distant organs that promotes angiogenesis, reshaping extracellular matrix, forming immunosuppressive environment and other ways to form appropriate pre-metastasis niche. Here, we explore the mechanism of localization and metastasis of pancreatic cancer and use sEVs as early biomarkers for the detection and treatment of pancreatic cancer. Graphical Abstract

The role of platelets in tumor cell metastasis

Platelets are small, nuclear-free cells whose main function is to stop bleeding. In addition to performing a hemostatic function, platelets are also involved in immune and inflammatory processes. Extensive experimental data suggest that platelets support tumor metastasis and their activation plays a critical role in cancer progression. In the circulatory system, platelets protect tumor cells from immune elimination and promote their arrest at the endothelium, supporting the formation of secondary lesions. Due to the significant contribution of platelets to tumor cells survival and propagation, antithrombotic drugs are considered as a novel anti-metastasis approach. In this article, the authors set a goal to summarize and update the currently existing knowledge about the molecular mechanisms and the role of platelets-tumor cells interaction, as well as to discuss the possibility of platelets receptors as anti-metastasis targets.

Galloflavin Relieves the Malignant Behavior of Colorectal Cancer Cells in the Inflammatory Tumor Microenvironment

Background: In this study, we mainly aimed to explore the correlation between galloflavin and NLRP3 and its effect on colorectal cancer.Methods: NLRP3 was overexpressed in SW480 cells; LPS + ATP was used to mimic the inflammatory microenvironment. Wound healing assay and Transwell assay were utilized to detect cell migration and invasion abilities; CCK-8 assay was performed to detect cell viability alterations; colony formation assay was conducted to detect colony formation ability; Western blot was used to detect the levels of NLRP3, ASC, C-Myc, and P21. SW480 cells were pretreated with high-dose and low-dose galloflavin, followed by observation of their effects on cell metastasis and invasion. NLRP3 was knocked out in SW480 to construct the SW480-NLRP3−/− cell line, followed by high-dose galloflavin treatment and subsequent observation of cell metastasis and invasion abilities. Small molecule–protein docking and pull-down assay were performed to confirm the targeting relationship between galloflavin and NLRP3. After constructing a tumor-bearing mice model, galloflavin was intragastrically administered, followed by detection of tumor growth, expression of NLRP3 and ASC by immunohistochemistry, and tumor histopathology by H&E staining.Results: After NLRP3 overexpression and LPS/ATP induction in SW480, the cell migration and invasion abilities were significantly enhanced, and cell viability was also enhanced. The activation of NLRP3 could promote the malignant behavior of colorectal cancer cells in the inflammatory microenvironment. Galloflavin treatment could significantly attenuate the malignant behavior of SW480 in the inflammatory microenvironment and inhibit the migration and invasion capabilities of SW480. The knockout of NLRP3 inhibited the effect of galloflavin, which did not significantly change the migration and invasion abilities. Molecular docking and pull-down assay revealed a targeted binding relationship between galloflavin and NLRP3 and that galloflavin is bound to NLRP3 not ASC protein. Moreover, galloflavin could inhibit tumor growth and decrease the expression of NLRP in tumor-bearing mice.Conclusion: In this study, we found that NLRP3 could promote the migration and invasion of colorectal cancer cells in the inflammatory microenvironment. Galloflavin could inhibit the malignant behavior of colorectal cancer cells by targeting NLRP3.

Exosomal circRNAs: Emerging Players in Tumor Metastasis

Metastasis is an important feature of malignant tumors, and is the primary cause of poor prognosis and treatment failure, in addition to representing a potentially fatal challenge for cancer patients. Exosomes are small extracellular vesicles 30–150 nm in diameter that transmit cargo, such as DNA, RNA, and proteins, as a means of intercellular communication. Exosomes play crucial roles in a range of human diseases, especially malignant tumors. A growing number of studies have verified that circRNAs can be enveloped in exosomes and transferred from secretory cells to recipient cells, thereby regulating tumor progression, especially tumor metastasis. Exosomal circRNAs regulate tumor cell metastasis not only by regulating the signaling pathways, but also by affecting the tumor microenvironment. Moreover, exosomal circRNAs have the potential to serve as valuable diagnostic biomarkers and novel therapeutic targets in cancer patients. In this review, we summarize the mechanism by which exosomal circRNAs modulate metastatic phenomena in various types of tumors, and put forward the prospects of clinical applications of exosomal circRNAs in tumor therapy.

Inhibition of AMPK/PFKFB3 Mediated Glycolysis Synergizes with Penfluridol to Suppress Gallbladder Cancer Growth

Background Penfluridol (PF) is an FDA approved antipsychotic drug, which shows anticancer activity recently. However, the anticancer effects and underlying mechanisms of PF on gallbladder cancers (GBCs) is not well-established. Methods Herein, cytotoxicity, cell proliferation, cell apoptosis, and cell metastasis assays were used to investigate the anticancer activity of PF on GBCs. Glucose consumption and lactic production assays were used to detect the glycolysis alteration. Western blotting was used to detect the corresponding signaling change after PF treatment. Nude mice were utilized to study the anticancer activity of PF in vivo. Results Here, we first observed that PF significantly suppress GBC cells proliferation and metastasis. After PF treatment, the glucose consumption and lactic production of GBCs were significantly increased. In addition, we found that inhibition of glycolysis enhanced the anticancer activity of PF. Further studies demonstrated that glycolysis was medicated by the activation of AMPK/PFKFB3 signaling pathway. Mechanistically, we demonstrated that AMPK/PFKFB3 signaling pathway mediated glycolysis was a resistant mechanism of PF in GBCs. Conclusions Inhibition of AMPK enhanced the anticancer effects of PF on GBCs. therefore, our studies provided a novel insight into repurposing PF as anticancer agent for GBCs, and AMPK inhibition in combination with PF could be a potential therapeutic approach for GBCs.

Hippo signaling suppresses tumor cell metastasis via a Yki-Src42A positive feedback loop

Metastasis is an important cause of death from malignant tumors. It is of great significance to explore the molecular mechanism of metastasis for the development of anti-cancer drugs. Here, we find that the Hippo pathway hampers tumor cell metastasis in vivo. Silence of hpo or its downstream wts promotes tumor cell migration in a Yki-dependent manner. Furthermore, we identify that inhibition of the Hippo pathway promotes tumor cell migration through transcriptional activating src42A, a Drosophila homolog of the SRC oncogene. Yki activates src42A transcription through direct binding its intron region. Intriguingly, Src42A further increases Yki transcriptional activity to form a positive feedback loop. Finally, we show that SRC is also a target of YAP and important for YAP to promote the migration of human hepatocellular carcinoma cells. Together, our findings uncover a conserved Yki/YAP-Src42A/SRC positive feedback loop promoting tumor cell migration and provide SRC as a potential therapeutic target for YAP-driven metastatic tumors.