ARID1A loss induces P4HB to activate fibroblasts to support lung cancer cell growth, invasion, and chemoresistance.

Loss of AT-interacting domain-rich protein 1A (ARID1A) frequently occurs in human malignancies including lung cancer. The biological consequence of ARID1A mutation in lung cancer is not fully understood. This study was designed to determine the effect of ARID1A-depleted lung cancer cells on fibroblast activation. Conditioned media was collected from ARID1A-depleted lung cancer cells and employed to treat lung fibroblasts. The proliferation and migration of lung fibroblasts were investigated. The secretory genes were profiled in lung cancer cells upon ARID1A knockdown. Antibody-based neutralization was utilized to confirm their role in mediating the cross-talk between lung cancer cells and fibroblasts. NOD-SCID-IL2RgammaC-null (NSG) mice received tumor tissues from patients with ARID1A-mutated lung cancer to establish patient-derived xenograft (PDX) models. Notably, ARID1A-depleted lung cancer cells promoted the proliferation and migration of lung fibroblasts. Mechanistically, ARID1A depletion augmented the expression and secretion of prolyl 4-hydroxylase beta (P4HB) in lung cancer cells, which induced the activation of lung fibroblasts through the ß-catenin signaling pathway. P4HB-activated lung fibroblasts promoted the proliferation, invasion, and chemoresistance in lung cancer cells. Neutralizing P4HB hampered the tumor growth and increased cisplatin cytotoxic efficacy in two PDX models. Serum P4HB levels were higher in ARID1A-mutated lung cancer patients than in healthy controls. Moreover, increased serum levels of P4HB were significantly associated with lung cancer metastasis. Together, our work indicates a pivotal role for P4HB in orchestrating the cross-talk between ARID1A-mutated cancer cells and cancer-associated fibroblasts during lung cancer progression. P4HB may represent a promising target for improving lung cancer treatment.

Evaluating the value of progressive muscle relaxation therapy for patients with lumbar disc herniation after surgery based on a difference-in-differences model.

We evaluate the value of progressive muscle relaxation (PMR) for patients with lumbar disc herniation after surgery based on a difference-in-differences model. A total of 128 patients with lumbar disc herniation who underwent surgery were randomly assigned to undergo either conventional intervention (conventional intervention group, n = 64) or conventional intervention combined with PMR (PMR group, n = 64). Perioperative anxiety level, stress level and lumbar function were compared between the two groups and compared pain between the two groups before and 1 week and 1 and 3 months after surgery. After 3 months, no one was lost to follow-up. At 1 day before surgery and 3 days after surgery, Self-rating Anxiety Scale score in the PMR group was significantly lower than that in the conventional intervention group (P < 0.05). At 30 min before surgery, heart rate and systolic blood pressure in the PMR group were significantly lower than those in the conventional intervention group (P < 0.05). After intervention, the scores of subjective symptoms, clinical signs and restrictions on activities of daily living were significantly higher in the PMR group than those in the conventional intervention group (all P < 0.05). Visual Analogue Scale score in the PMR group was significantly lower than that in the conventional intervention group (all P < 0.05). The amplitude of change in VAS score in the PMR group was greater than that in the conventional intervention group (P < 0.05). PMR can relieve perioperative anxiety and stress in patients with lumbar disc herniation, reduce postoperative pain and improve lumbar function.

Gene Targets Network Analysis for the Revealing and Guidance of Molecular Driving Mechanism of Lung Cancer.

The objective was to explore the function of gene differential expressions between lung cancer tissues and the interaction between the relevant encoded proteins, thereby analyzing the important genes closely related to lung cancer. A total of 120 samples from the GEO database (including two groups, i.e., 60 lung cancer in situ specimens and 60 normal specimens) were taken as the research objects, which were submitted to the analysis of signaling pathway, biological function enrichment, and protein interactions to reveal the molecular driving mechanism of lung cancer. Results: A total of 875 differentially expressed genes were obtained, including 291 up-regulated genes and 584 down-regulated genes. The up-regulated genes were mainly involved in biological processes such as protein metabolism, protein hydrolysis, mitosis, and cell division. Down-regulated genes were mainly involved in neutrophil chemotaxis, inflammatory response, immune response, and angiogenesis. The protein expression of high expression genes and low expression genes in patients were higher than those in the control group. The protein corresponding to the high expression gene was highly expressed in the patient group. Meanwhile, the proteins corresponding to the low expression genes were also expressed in the patient group, which showed that although the proteins corresponding to the low expression genes were low in the patients, they were still the target genes related to lung cancer. In conclusion, the molecular driving mechanism in lung cancer was mainly related to protein metabolism, proteolysis, mitosis, and cell division. It was found that TOP2A, CCNB1, CCNA2, CDK1, and TTK might be the critical target genes of lung cancer.

MicroRNA-155 silencing enhances inflammatory response and lipid uptake in oxidized low-density lipoprotein-stimulated human THP-1 macrophages.

It has been proposed that the inflammatory response of monocytes/macrophages induced by oxidized low-density lipoprotein (oxLDL) is a key event in the pathogenesis of atherosclerosis. MicroRNA-155 (miR-155) is an important regulator of the immune system and has been shown to be involved in acute inflammatory response. However, the function of miR-155 in oxLDL-stimulated inflammation and atherosclerosis remains unclear. Here, we show that the exposure of human THP-1 macrophages to oxLDL led to a marked up-regulation of miR-155 in a dose-dependent manner. Silencing of endogenous miR-155 in THP-1 cells using locked nucleic acid-modified antisense oligonucleotides significantly enhanced oxLDL-induced lipid uptake, up-regulated the expression of scavenger receptors (lectinlike oxidized LDL receptor-1, cluster of differentiation 36 [CD36], and CD68), and promoted the release of several cytokines including interleukin (IL)-6, -8, and tumor necrosis factor α (TNF-α). Luciferase reporter assay showed that targeting miR-155 promoted nuclear factor-kappa B (NF-κB) nuclear translocation and potentiated the NF-κB-driven transcription activity. Moreover, miR-155 knockdown resulted in a marked increase in the protein amount of myeloid differentiation primary response gene 88 (MyD88), an important adapter protein used by Toll-like receptors to activate the NF-κB pathway. Our data demonstrate that miR-155 serves as a negative feedback regulator in oxLDL-stimulated THP-1 inflammatory responses and lipid uptake and thus might have potential therapeutic implications in atherosclerosis.