In this study we have demonstrated that both CD44 (the hyaluronan (HA) receptor) and c-Src kinase are expressed in human ovarian tumor cells (SK-OV-3.ipl cell line), and that these two proteins are physically associated as a complex in vivo. Using a recombinant cytoplasmic domain of CD44 and an in vitro binding assay, we have detected a specific interaction between CD44 and c-Src kinase. Furthermore, the binding of HA to SK-OV-3.ipl cells promotes c-Src kinase recruitment to CD44 and stimulates c-Src kinase activity, which, in turn, increases tyrosine phosphorylation of the cytoskeletal protein, cortactin. Subsequently, tyrosine phosphorylation of cortactin attenuates its ability to cross-link filamentous actin in vitro. In addition, transfection of SK-OV-3.ipl cells with a dominant active form of c-Src (Y527F)cDNA promotes CD44 and c-Src association with cortactin in membrane projections, and stimulates HA-dependent/CD44-specific ovarian tumor cell migration. Finally, overexpression of a dominant-negative mutant of c-Src kinase (K295R) in SK-OV-3.ipl cells impairs the tumor cell-specific phenotype. Taken together, these findings strongly suggest that CD44 interaction with c-Src kinase plays a pivotal role in initiating cortactin-regulated cytoskeleton function and HAdependent tumor cell migration, which may be required for human ovarian cancer progression.The cell adhesion molecule, CD44, is one of the major hyaluronic acid (HA) 1 receptors (1-3). It belongs to a family of transmembrane glycoproteins which contain a variable extracellular domain, a single spanning 23-amino acid transmembrane domain, and a 70-amino acid cytoplasmic domain (4). Nucleotide sequence analyses reveal that many CD44 isoforms (derived from alternative splicing mechanisms) are variants of the standard form, CD44s (4). CD44s (molecular mass ϳ85 kDa) is the most common isoform of CD44 found in many cell types including human ovarian carcinoma cells (5-9). The presence of high levels of CD44s (often together with CD44v) is emerging as an important metastatic tumor marker in a number of carcinomas, and is also implicated in the unfavorable prognosis of a variety of cancers including human ovarian cancers (5-9).The invasive phenotype of CD44s-positive epithelial tumor cells has been linked to HA-mediated CD44 signaling and cytoskeletal activation. CD44s contains several HA-binding sites in their extracellular domain (1-3). The binding of HA to CD44s causes cells to adhere to the extracellular matrix (ECM) components (1-3), and has also been implicated in the stimulation of several different biological activities (10 -16). The intracellular domain of CD44 binds to signaling proteins such as RhoGTPases (e.g. RhoA) (17); Tiam1, a guanine nucleotide exchange factor for Rac1 (18); and cytoskeletal proteins, including ankyrin (2,3,9,(17)(18)(19)(20)(21) and the ERM proteins (ezrin, radixin, and moesin) (23). Recent studies indicate that the binding of ECM components (e.g. HA) promote CD44-mediated Tiam1-Rac1 signaling and cytoskeleton function lea...
Circular RNA (circRNA) is a type of noncoding RNA that can interact with miRNAs to regulate gene expression. However, little is known concerning circRNA, which is crucial in the pathogenesis of lung cancer. To date, limited studies have explored the role of circ_0044516 in lung cancer progression. Recently, we observed that circ_0044516 expression levels were obviously elevated in lung cancer tissues and cells. A549 and SPCA1 cells were transfected with circ_0044516 siRNA. We observed that knockdown of circ_0044516 dramatically repressed cell proliferation, increased cell apoptosis, and repressed the cell cycle. Moreover, A549 and SPCA1 cell migration and invasion abilities were greatly repressed by circ_0044516 siRNA. Due to accumulating evidence demonstrating the vital role of cancer stem cells, their mechanism of involvement has drawn increasing attention in tumor progression and metastasis research. We also found that cancer stem cell properties were restrained by silencing circ_0044516 in A549 and SPC-A1 cells. Moreover, in vivo xenograft experiments showed that circ_0044516 downregulation reduced tumor growth. Mechanistically, in lung cancer and using bioinformatics, we demonstrated that circ_0044516 sponges miR-136 targeting MAT2A. Furthermore, rescue assays were carried out to identify that circ_0044516 modulates cell proliferation, invasion, and stemness by regulating miR-136 and MAT2A in lung cancer. In summary, our study revealed that the circ_0044516/miR-136/MAT2A axis is involved in lung cancer progression. Our findings may provide novel targets for diagnosis and therapeutic intervention in lung cancer patients.
Background: Lung cancer is a common malignant neoplasm worldwide. Phosphoinositide-3-kinase, regulatory subunit 1 (PIK3R1) plays as a therapeutic target in many cancers. The role PIK3R1 plays in lung cancer still remains unclear. Our study aims to explore the role of PIK3R1 in lung cancer.Methods: We used quantitative real-time PCR (qPCR) to detect the PIK3R1 mRNA expression level in our 20 paired lung cancer patients. We then used A549sh-PIK3R1, H1299sh-PIK3R1, H1650LV-PIK3R1, H292LV-PIK3R1, A549sh-PIK3R1+LV-PIK3R1 and H1299sh-PIK3R1+LV-PIK3R1 cells for in vitro analysis. Cell viability assay was used to detect the ability of PIK3R1 in regulating proliferation of lung cancer. Western blot analysis was used to detect the PIK3R1 protein expression level and proteins in PI3K/AKT/mTOR signaling pathway.Results: PIK3R1 mRNA expression level was higher in tumour tissues than the corresponding adjacent noncancerous among the 20 lung cancer patients. Increased PIK3R1 promoted lung cancer proliferation and downregulated PIK3R1 inhibited lung cancer proliferation. Furthermore, PIK3R1 downregulation suppressed p-PI3K, p-Akt, and p-mTOR in A549sh-PIK3R1 and H1299sh-PIK3R1 cells. Overexpressed of PIK3R1 upregulated p-PI3K, p-Akt, and p-mTOR in H1650LV-PIK3R1 and H292LV-PIK3R1 cells. Cell viability was increased in both A549 and H1299 cells following sh-PIK3R1+LV-PIK3R1 co-transfection, thus reversed the effect of sh-PIK3R1 on cell proliferation.Conclusions: We identified that overexpressed of PIK3R1 could promote lung cancer proliferation via PI3K/AKT/mTOR signaling pathway, thus may provide PIK3R1 as a therapeutic target for effective strategy in lung cancer.
Introduction: Chronic obstructive pulmonary disease (COPD) is a common high-burden and highly disabling lung disease. The quality of life and exercise endurance of patients with COPD is often low because of atrophy of the respiratory and skeletal muscles. Although recommended by the global initiative for chronic obstructive lung disease guidelines, pulmonary rehabilitation (PR) has not been used widely because of its inherent limitations. Tuna-Hui-Chun-Gong (TNHCG) is a popular traditional exercise used to treat COPD in China. We aim to evaluate the safety and efficacy of TNHCG for PR of COPD. Methods: The provided protocol is for a single-blind randomized controlled trial in which 120 COPD patients will be randomly and equally divided into the experimental or control group. The control group will be treated with standard COPD drugs while the experimental group will perform TNHCG exercises apart from standard drug treatment. The duration of treatment will be 24 weeks and a follow-up for 48 weeks. The primary outcome will be the 6-Minute Walk Test. The secondary outcomes will include the pulmonary function test, St George's respiratory questionnaire, COPD assessment test, modified medical research council dyspnea scale, Hospital Anxiety and Depression Scale, and exacerbation frequency. A safety assessment will also be performed during the trial. Discussion: Our study will provide evidence to support TNHCG exercise as an additional measure for PR of COPD. Trial registration: ChiCTR1900028332, Registered December 29, 2019. Ethics and dissemination: Ethics approval has been granted by the Sichuan Traditional Chinese Medicine Regional Ethics Review Committee (No. 2019KL-050).
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