Journal of Cell Communication and Signaling最新文献

The objective of this study was to elucidate the involvement of the long noncoding RNA (lncRNA) HOTTIP in acute lung injury and understand the underlying mechanisms. Relevant expression of mRNAs and proteins were assessed by qRT-PCR and western blot assays. Cell viability was determined by employing the CCK-8 assay, and apoptosis was quantified through TUNEL staining. The concentration of inflammatory factors was measured by ELISA. The degree of DNA methylation was quantified through MSP assay. The interaction between HOTTIP and DNA methyltransferase 1 (DNMT1) was examined by RIP assay. LPS upregulated HOTTIP, whereas downregulated SP-C level in AEC II cells. HOTTIP knockdown inhibited LPS-induced apoptosis and the secretion of inflammatory cytokines (TNF-α, IL-1β and IL-6) in AEC II cells. Mechanistically, HOTTIP recruited DNMT1 to the SP-C promoter, thereby facilitating DNA methylation of SP-C and suppressing its expression. Additionally, inhibitory of SP-C reversed the effects of HOTTIP or DNMT1 knockdown on apoptosis and inflammation in AEC II cells induced by LPS. HOTTIP recruited DNMT1 to epigenetically inhibit SP-C expression, leading to the promotion of lung epithelial cell injury caused by LPS, suggesting that targeting HOTTIP may be an effective strategy for the therapy of lung epithelial cell injury.

Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are bioactive phospholipids that act as mitogens in various cancers. Both LPA and S1P activate G-protein coupled receptors (GPCRs). We examined the role of CCN1/CYR61, an inducible matricellular protein, in LPA-induced signal transduction in PC-3 human prostate cancer cells. We found that both LPA and S1P induced expression of CCN1 and CCN2 within 2–4 h. CCN1 was induced by 18:1-LPA, but not by 18:0-, 18:2-, or 18:3-LPAs. A free fatty acid receptor-4 agonist inhibited LPA-induced CCN1 induction. CCN1 appeared in the ECM within 2 h after LPA addition. LPA caused biphasic activation of Erk MAPK, with an initial peak at 10–20 min followed by a later phase after 6 h. LPA increased adhesion of PC-3 cells to culture substrates (standard culture plates, fibronectin, or extracellular matrix) at 2 h, an intermediate event between early and late LPA signals. Knockdown of CCN1 suppressed LPA-induced adhesion to ECM or fibronectin. ECM from CCN1 knockdown cells was a poor substrate for adhesion, as compared to ECM from control cells. These results suggest that CCN1 contributes to LPA responses in the tumor microenvironment. The LPA-CCN1 axis holds promise for the development of novel therapeutic strategies in cancer.

CD38 is the main NADase in mammalian cells. It regulates the homeostasis of nicotinamide adenine dinucleotide (NAD+) and extracellular nucleotides. Its function plays an important role in infection and aging. However, its potential functions in tumor cells have not been fully elucidated. In the present study, we demonstrated that lactate, which is derived from tumor metabolism remodeling, upregulates the expression of CD38 through OXPHOS-driven Hippo-TAZ pathway. The highly expressed CD38 converts NAD + to adenosine through the CD203a/CD73 complex and adenosine binds and activates its receptor A2AR, inducing the expression of Snail and promoting the invasion and metastasis of lung cancer cells. This finding elucidates a new perspective on the interplay between NAD + metabolism and glycolysis in tumor development.

Long noncoding RNAs (lncRNAs) are involved in regulatory processes in laryngeal squamous cell carcinoma (LSCC) at posttranscriptional epigenetic modification level. Yet, the function and underlying mechanism behind lncRNA AC004943.2 in LSCC is still obscure. Therefore, the potential role of AC004943.2 in LSCC progression was investigated. The expression of gene or protein was tested by real-time quantitative polymerase chain reaction and western blot. MTT, colony formation, wound healing, and transwell experiments were applied to detect LSCC cell viability, proliferation, migration and invasion, respectively. The interaction among AC004943.2, miR-135a-5p, and protein tyrosine kinase 2 (PTK2) were analyzed by bioinformatics prediction and luciferase assay. AC004943.2 was highly expressed in LSCC cells compared with normal human bronchial epithelial cells, while miR-135a-5p was lowly expressed. AC004943.2 knockdown or miR-135a-5p overexpression inhibited LSCC cell viability, proliferation, migration and invasion. Mechanistically, AC004943.2 increased PTK2 expression in LSCC cells by sponging miR-135a-5p. Furthermore, miR-135a-5p knockdown inverted the inhibitory effect of AC004943.2 silencing on LSCC cell malignant behaviors. MiR-135a-5p upregulation attenuated the PTK2/PI3K pathway to inhibit progression of LSCC. AC004943.2 facilitated the cancerous phenotypes of LSCC cells by activating the PTK2/PI3K pathway through targeting miR-135a-5p, which furnished a therapeutic candidate for LSCC treatment.

Gastric cancer (GC) is one of the most common solid cancers with high incidence and mortality worldwide. Chronic gastritis and consequent inflammatory microenvironment is known as a major cause leading to gastric carcinogenesis. Here we report that PIK3CD that encodes p110δ, a catalytic subunit of the class IA PI3Ks, is overexpressed and tumorigenic in GC and associated with tumor inflammatory microenvironment. By investigating the data from TCGA database and our immunohistochemical staining and quantitative real-time PCR results from clinical samples, we found PIK3CD exhibits higher expression level in GC tissues compared with adjacent non-tumorous stomach tissues. Genetic silencing of PIK3CD in GC cells retards proliferation and migration in vitro and tumorigenicity and metastasis in vivo. In contrast, enhanced expression of PIK3CD promotes these phenotypes in vitro. Furthermore, pharmacological inhibition of PIK3CD could reduce GC cell viability and colony formation capacities. More importantly, we reveal a relevant mechanism that PIK3CD, but not PIK3CA and PIK3CB, is transcriptionally regulated by the pro-inflammatory IL2/JAK3/STAT5 axis and tumor-infiltrating immune cells such as lymphocytes. These observations may setup a new crosstalk between tumor inflammatory microenvironment, IL2/JAK3/STAT5 signaling and PI3K/AKT signaling. Targeting PIK3CD may be a promising therapy strategy for GC.

Persistent activation of hepatic stellate cells (HSCs) in the injured liver leads to the progression of liver injury from fibrosis to detrimental cirrhosis. In a previous study, we have shown that survivin protein is upregulated during the early activation of HSCs, which triggers the onset of liver fibrosis. However, the therapeutic potential of targeting survivin in a fully established fibrotic liver needs to be investigated. In this study, we chemically induced hepatic fibrosis in mice using carbon tetrachloride (CCl4) for 6 weeks, which was followed by treatment with a survivin suppressant (YM155). We also evaluated survivin expression in fibrotic human liver tissues, primary HSCs, and HSC cell line by histological analysis. αSMA⁺ HSCs in human and mice fibrotic liver tissues showed enhanced survivin expression, whereas the hepatocytes and quiescent (qHSCs) displayed minimal expression. Alternatively, activated M2 macrophage subtype induced survivin expression in HSCs through the TGF-β-TGF-β receptor-I/II signaling. Inhibition of survivin in HSCs promoted cell cycle arrest and senescence, which eventually suppressed their activation. In vivo, YM155 treatment increased the expression of cell senescence makers in HSCs around fibrotic septa such as p53, p21, and β-galactosidase. YM155 treatment in vivo also reduced the hepatic macrophage population and inflammatory cytokine expression in the liver. In conclusion, downregulation of survivin in the fibrotic liver decreases HSC activation by inducing cellular senescence and modulating macrophage cytokine expression that collectively ameliorates liver fibrosis.

Protein–protein interactions (PPIs) play a crucial role in various biological processes by establishing domain–motif (DMI) and domain–domain interactions (DDIs). While the existence of real DMIs/DDIs is generally assumed, it is rarely tested; therefore, this study extensively compared high-throughput methods and public PPI repositories as sources for DMI and DDI prediction based on the assumption that the human interactome provides sufficient data for the reliable identification of DMIs and DDIs. Different datasets from leading high-throughput methods (Yeast two-hybrid [Y2H], Affinity Purification coupled Mass Spectrometry [AP-MS], and Co-fractionation-coupled Mass Spectrometry) were assessed for their ability to capture DMIs and DDIs using known DMI/DDI information. High-throughput methods were not notably worse than PPI databases and, in some cases, appeared better. In conclusion, all PPI datasets demonstrated significant enrichment in DMIs and DDIs (p-value <0.001), establishing Y2H and AP-MS as reliable methods for predicting these interactions. This study provides valuable insights for biologists in selecting appropriate methods for predicting DMIs, ultimately aiding in SLiM discovery.

GREMLIN1 (GREM1) is member of a family of structurally and functionally related secreted cysteine knot proteins, which act to sequester and inhibit the action of multifunctional bone morphogenetic proteins (BMPs). GREM1 binds directly to BMP dimers, thereby preventing BMP-mediated activation of BMP type I and type II receptors. Multiple reports identify the overexpression of GREM1 as a contributing factor in a broad range of cancers. Additionally, the GREM1 gene is amplified in a rare autosomal dominant inherited form of colorectal cancer. The inhibitory effects of GREM1 on BMP signaling have been linked to these tumor-promoting effects, including facilitating cancer cell stemness and the activation of cancer-associated fibroblasts. Moreover, GREM1 has been described to bind and signal to vascular endothelial growth factor receptor (VEGFR) and stimulate angiogenesis, as well as epidermal and fibroblast growth factor receptor (EGFR and FGFR) to elicit tumor-promoting effects in breast and prostate cancer, respectively. In contrast, a 2022 report revealed that GREM1 can promote an epithelial state in pancreatic cancers, thereby inhibiting pancreatic tumor growth and metastasis. In this commentary, we will review these disparate findings and attempt to provide clarity around the role of GREM1 signaling in cancer.

Cellular communication network factor 2 (CCN2) molecules promote endochondral ossification and articular cartilage regeneration, and circular RNAs (circRNAs), which arise from various genes and regulate gene expression by adsorbing miRNAs, are known to be synthesized from CCN2 in human vascular endothelial cells and other types of cells. However, in chondrocytes, not only the function but also the presence of CCN2-derived circRNA remains completely unknown. In the present study, we investigated the expression and function of CCN2-derived circRNAs in chondrocytes. Amplicons smaller than those from known CCN2-derived circRNAs were observed using RT-PCR analysis that could specifically amplify CCN2-derived circRNAs in human chondrocytic HCS-2/8 cells. The nucleotide sequences of the PCR products indicated novel circRNAs in the HCS-2/8 cells that were different from known CCN2-derived circRNAs. Moreover, the expression of several Ccn2-derived circRNAs in murine chondroblastic ATDC5 cells was confirmed and observed to change alongside chondrocytic differentiation. Next, one of these circRNAs was knocked down in HCS-2/8 cells to investigate the function of the human CCN2-derived circRNA. As a result, CCN2-derived circRNA knockdown significantly reduced the expression of aggrecan mRNA and proteoglycan synthesis. Our data suggest that CCN2-derived circRNAs are expressed in chondrocytes and play a role in chondrogenic differentiation. Production and role of CCN2-derived RNAs in chondrocytes.

The unfolded protein response (UPR) is a cellular mechanism that protects cells during stress conditions in which there is an accumulation of misfolded proteins in the endoplasmic reticulum (ER). UPR activates three signaling pathways that function to alleviate stress conditions and promote cellular homeostasis and cell survival. During unmitigated stress conditions, however, UPR activation signaling changes to promote cell death through apoptosis. Interestingly, cancer cells take advantage of this pathway to facilitate survival and avoid apoptosis even during prolonged cell stress conditions. Here, we discuss different signaling pathways associated with UPR and focus specifically on one of the ER signaling pathways activated during UPR, inositol-requiring enzyme 1α (IRE1). The rationale is that the IRE1 pathway is associated with cell fate decisions and recognized as a promising target for cancer therapeutics. Here we discuss IRE1 inhibitors and how they might prove to be an effective cancer therapeutic.