Background Chronic inflammation plays a significant role in the occurrence and development of non-small cell lung cancer (NSCLC). Hydroxysafflor yellow A (HSYA), a chemical compound of the yellow color pigments extracted from the safflower, has been widely used in clinical treatment with positive antioxidation, anti-inflammation, and antitumor effects. However, the role and underlying mechanisms of HYSA on development and progress in inflammation-mediated NSCLC are unknown. Methods Cell counting kit-8, colony formation, EdU, cell apoptosis, wound healing, Transwell migration and invasion, and enzyme-linked immunosorbent assays; flow cytometry; and Western blotting were conducted using human NSCLC cell lines A549 and H1299. Results Lipopolysaccharide (LPS) significantly promoted the proliferation and enhanced colony formation of A549 and H1299 cells, while HYSA notably reversed the effects of LPS. HYSA induced apoptosis of LPS-mediated A549 and H1299 cells in a dose dependent manner; and remarkably suppressed migration, invasion, and epithelial-mesenchymal transition (EMT), significantly regulated production of LPS-induced inflammation cytokines, and downregulated protein expression of PI3K/Akt/mTOR and ERK/MAPK signaling pathways in LPS-induced A549 and H1299 cells. Furthermore, PI3K (LY294002) and ERK (SCH772984) inhibitors remarkably inhibited proliferation, migration, invasion, and EMT, and induced apoptosis in LPS-mediated A549 and H1299 cells. These effects were even more obvious in the presence of HYSA and LY294002 or SCH772984 compared to those of either agent alone. Conclusion HYSA suppressed LPS-mediated proliferation, migration, invasion, and EMT in A549 and H1299 cells by inhibiting the PI3K/Akt/mTOR and ERK/MAPK signaling pathways, indicating that HYSA may be a potential candidate to treat inflammation-mediated NSCLC.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/1759-7714.13019

Hydroxysafflor yellow A inhibited lipopolysaccharide-induced non-small cell lung cancer cell proliferation, migration, and invasion by suppressing the PI3K/AKT/mTOR and ERK/MAPK signaling pathways

Non-small cell lung cancer (NSCLC) is the leading cause of death by cancer worldwide. Despite developments in therapeutic approaches for the past few decades, the 5-year survival rate of patients with NSCLC remains low. NSCLC tumor is a complex, heterogeneous microenvironment, comprising blood vessels, cancer cells, immune cells, and stroma cells. Vascular endothelial growth factors (VEGFs) are a major mediator to induce tumor microvasculature and are associated with the progression, recurrence, and metastasis of NSCLC. Current treatment medicines targeting VEGF/VEGF receptor (VEGFR) pathway, including neutralizing antibodies to VEGF or VEGFR and receptor tyrosine kinase inhibitors, have shown good treatment efficacy in patients with NSCLC. VEGF is not only an important angiogenic factor but also an immunomodulator of tumor microenvironment (TME). VEGFs can suppress antigen presentation, stimulate activity of regulatory T (Treg) cells, and tumor-associated macrophages, which in turn promote an immune suppressive microenvironment in NSCLC. The present review focuses on the angiogenic and non-angiogenic functions of VEGF in NSCLC, especially the interaction between VEGF and the cellular components of the TME. Additionally, we discuss recent preclinical and clinical studies to explore VEGF/VEGFR-targeted compounds and immunotherapy as novel approaches targeting the TME for the treatment of NSCLC.

VEGF/VEGFR-Targeted Therapy and Immunotherapy in Non-small Cell Lung Cancer: Targeting the Tumor Microenvironment

Runt-related transcription factor 1 (RUNX1) is frequently involved in the progression of acute leukemia. However, emerging and discoverable RUNX1 somatic mutations, RUNX1 expressional signatures in normal tissues and cancers, and RUNX1's clinical significance in many cancer types have attracted attention for considering RUNX1 as a biomarker for cancer. Recent discoveries have demonstrated the indirect and direct biological functions of RUNX1 in modulating cancer metastasis, proliferation, angiogenesis, cancer stemness and chemoresistance to anticancer drugs, warranting the further investigations of the underlying mechanisms to provide knowledge for developing a novel therapeutic approach. In this review article, we focused mainly on recent research developments involving oncogenic activities of RUNX1 by summarizing and integrating RUNX1 somatic mutations, clinical trials, transcriptome data, clinical information and the discoveries related to the RUNX1-induced signaling pathway in modulating malignant phenotypes. Furthermore, a comprehensive demonstration of RUNX1 RNA expression in a pancancer panel and specific normal cell types at single-cell level were presented, and the results suggest potential sites and cell types of RUNX1-related tumorigenesis. With this review, we aim to shed light on the understanding of the regulatory role of RUNX1 in cancer progression, and provide information for guiding potential research directions in this field. 

RUNX1 and cancer.

Background Non-small cell lung cancer (NSCLC) seriously endangers human health. Circular RNAs (circRNAs) regulate diverse types of cancers, including NSCLC. This study investigated the possible mechanism of circ0001313 in NSCLC. Materials and methods Circ0001313 expression in NSCLC tissues was measured, and its correlation with clinicopathological features was analyzed. The binding relationships among circ0001313, microRNA (miR)-452 and HMGB3 were tested. The gain and loss of functions were performed to examine NSCLC cell malignant behaviors. After HMGB3 overexpression, ERK/MAPK pathway-related protein levels were detected. Subsequently, the rescue experiment was further performed using an ERK/MAPK pathway inhibitor PD98059. Results Abnormally elevated circ0001313 and decreased miR-452 in NSCLC cells were observed. Circ0001313 silencing or miR-452 overexpression significantly reduced NSCLC cell proliferation and invasion. Circ0001313 competitively bound to miR-452 to upregulate HMGB3, thus promoting NSCLC cell growth. HMGB3 overexpression activated the ERK/MAPK pathway to contribute to NSCLC development. Conclusion We highlighted that silencing of circ0001313 blunted the ERK/MAPK pathway via the miR-452/HMGB3 axis, thereby inhibiting NSCLC cell proliferation and invasion.

/pdf/circular-rna-0001313-knockdown-suppresses-non-small-cell-1yrliuqzqi.pdf

Circular RNA 0001313 Knockdown Suppresses Non-Small Cell Lung Cancer Cell Proliferation and Invasion via the microRNA-452/HMGB3/ERK/MAPK Axis.

Regulation of RUNX proteins by long non-coding RNAs and circular RNAs in different cancers.

PIGF and Flt-1 on the surface of macrophages induces the production of TGF-β1 by polarized tumor-associated macrophages to promote lung cancer angiogenesis.

Lung cancer (LC) is one of the malignant tumors with growing morbidity and mortality. The involvement of runt-related transcription factor 1 (RUNX1) in LC patients has been elucidated. We intended to research mechanisms of RUNX1 and tartrate-resistant acid phosphatase 5 (ACP5) in LC. Firstly, ACP5 levels in LC tissues, paracancerous tissues, LC cells and tracheal epithelial cells were detected. RUNX1 overexpression plasmid and interference plasmid were constructed and transfected into 95C cells and A549 cells, respectively. The binding of RUNX1 to ACP5 promoter was tested. Additionally, the gain- and loss-of-function were performed to explore the effects of ACP5 and RUNX1 on LC biological process. The xenograft tumor in nude mice was constructed in vivo to verify in vitro results. Functional rescue experiment was performed by adding MAPK-specific activator P79350 to A549 cells with si-ACP5 to measure the effects of ERK/MAPK axis on LC progression. Consequently, we found ACP5 expression was higher in LC tissues and cells, and ACP5 silencing suppressed LC cell growth. Overexpression of ACP5 promoted malignant biological behavior of LC cells. RUNX1 could bind to ACP5 promoter, and overexpressed RUNX1 promoted ACP5 expression and LC cell growth. Moreover, ACP5 upregulated the ERK/MAPK axis and thus promoted LC progression. The results of xenograft tumor in nude mice showed that silencing ACP5 could inhibit the growth of LC cells in vivo. To conclude, silenced RUNX1 inhibits LC progression through the ERK/MAPK axis by binding to ACP5. This study may provide new approaches for LC treatment.

Runt-related transcription factor 1 contributes to lung cancer development by binding to tartrate-resistant acid phosphatase 5.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer death in both men and women. microRNAs (miRs) can exert important functions in cancer development. However, the role of miR-877 in NSCLC as it relates to tartrate resistant acid phosphatase 5 (ACP5) is unknown. For this study, the gain-and-loss-of-function experiments were performed to explore the effects of miR-877 and ACP5 on NSCLC. miR-877 expression in LC and paracancerous tissues, lung epithelial cell line and NSCLC cell lines was detected, and the association between miR-877 expression and clinical features of LC patients was analyzed. The levels of ACP5, epithelial-mesenchymal transition (EMT) markers and apoptosis-related proteins were measured. In vivo experiments were conducted for further validation. Consequently, we found that miR-877 expression was lowered in LC tissues and cell lines, and correlated with clinical stage, differentiation, lymph node metastasis and prognosis of NSCLC patients. Additionally, miR-877 was determined to inhibit ACP5 activity, and miR-877 downregulated the PI3K/AKT pathway by silencing ACP5. Furthermore, overexpression of miR-877 inhibited the viability, migration, invasion and EMT of NSCLC cells, but promoted cell apoptosis. In conclusion, miR-877 overexpression inhibited malignant biological behaviors of NSCLC cells by downregulating ACP5 and inactivating the PI3K/AKT pathway.

microRNA-877 contributes to decreased non-small cell lung cancer cell growth via the PI3K/AKT pathway by targeting tartrate resistant acid phosphatase 5 activity

Bicheng Fu

Papers

PIGF and Flt-1 on the surface of macrophages induces the production of TGF-β1 by polarized tumor-associated macrophages to promote lung cancer angiogenesis.

Runt-related transcription factor 1 contributes to lung cancer development by binding to tartrate-resistant acid phosphatase 5.

microRNA-877 contributes to decreased non-small cell lung cancer cell growth via the PI3K/AKT pathway by targeting tartrate resistant acid phosphatase 5 activity