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  • Cell stiffness is determined by the

    2022-10-02

    Cell stiffness is determined by the cytoskeleton, an intracellular polymeric network consisting of apomorphine filaments, microtubules, intermediate filaments, and crosslinking proteins [38]. Low cell stiffness has been correlated with reduced formation of well-defined F-actin filaments or bundles [39]. We observed a difference between the actin cytoskeleton arrangements of LCSCs exposed to shear stress and control cells, which may explain the effect of shear stress on cell stiffness. Moreover, our results showed that the FAK-ERK1/2 signalling pathway contributes to the change in cell stiffness induced by shear stress. Li et al. demonstrated that a decrease in cell elasticity affects the metastatic ability of cancer cells [41], and we have previously demonstrated that differences in cell cytoskeleton (F-actin) are accompanied by changes in the cell migration ability and Young's modulus. LCSCs with lower Young's modulus and higher migration ability had reduced and less organized cytoskeletons [2]. In that study, an increase in the migration ability of LCSCs was accompanied by a decrease in cell stiffness. These independent studies together suggest a relationship between cell stiffness and mobility. In contrast, our F-actin and cell stiffness data indicate that shear stress promotes LCSC migration by decreasing cell stiffness and enhancing the formation of F-actin. Similarly, our previous study demonstrated that salinomycin inhibits LCSC migration by increasing cell stiffness and the levels of filamentous actin [40].
    Introduction Lung cancer is the leading cause of cancer-related deaths worldwide in both men and women [1]. Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of lung cancers [2]. Compared with the steady increase in survival observed for most cancer types, advances in survival have been slow for lung cancers, which are typically diagnosed at an advanced stage, with 5-year survival rates of less than 18%. There is potential for lung cancer to be diagnosed at an earlier stage among high-risk individuals through the use of screening with low-dose computed tomography (LDCT). Approximately 90% of patients diagnosed with NSCLC die due to distant metastases rather than primary tumor, and metastasis has been a consistent problem in tumor prognosis and therapy [3], [4]. However, the complicated molecular and cellular mechanisms involved in lung cancer metastasis remain poorly understood. The need to identify potential therapeutic targets to improve NSCLC treatment is urgent. Ubiquitination is a posttranslational modification mechanism that regulates protein levels through proteasome-mediated proteolysis and that may also regulate localization, DNA integrity, chromatin remodeling, kinase signaling pathway activity, and others. Protein ubiquitination is orchestrated by the sequential activity of E1 ubiquitin-activating enzymes, E2 ubiquitin-conjugating enzymes and E3 ubiquitin ligases [5], [6]. More than 600 E3 ubiquitin ligases containing the regulators are expressed in the human genome, and catalyze the ubiquitination of proteins to target them for proteasomal degradation, which plays a critical role in the ubiquitin proteasome system [7], [8]. Additional evidence has indicated that E3 ubiquitin ligases are crucial for the initiation, promotion and progression of human cancers [9], [10], [11], [12]. However, only a few E3 ubiquitin ligases known to be involved in NSCLC metastasis have been reported. Squamous cell carcinoma-related oncogene (DCUN1D1/SCCRO) is a RING finger domain-containing ubiquitin E3 ligase, DCUN1D1 plays an important role in a variety of tumor proliferation and metastasis processes, such as cervical cancer, laryngeal squamous cell carcinoma, prostate cancer, colorectal cancer, squamous cell carcinomas and glioma [13], [14], [15], [16], [17], [18]. DCUN1D1 induces in NIH-3T3 cells invasion by activating MMP2 [19]. Prior studies have shown a high prevalence of overexpression of DCUN1D1 in NSCLC and have associated this with a more aggressive clinical course [20], [21]. However, there is still a lack of sufficient information about the role of DCUN1D1 in NSCLC. In our study, we found that the C-terminal Cullin binding domain leads to oncogenic activity and the UBA domain acts as a negative regulator of DCUN1D1 function in NSCLC. Moreover, DCUN1D1 activated the FAK oncogenic signaling pathway and upregulated PD-L1. This comprehensive analysis provides a foundation for the future functional and clinical assessment of DCUN1D1 in NSCLC.