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  • To date increasing evidence has demonstrated that dysregulat

    2022-01-03

    To date, increasing evidence has demonstrated that dysregulated lncRNAs are closely associated with the tumorigenesis and development of HCC via ceRNA modes [29,30]. LncRNAs could bind with special miRNAs and abrogate the inhibitory effect of these miRNAs on their targeted transcripts. For example, Wang et al. nutlin 3 showed that lncRNA cancer susceptibility candidate 2 (CASC2) promoted migration, invasion, and epithelial-to-mesenchymal transition (EMT) progression of HCC nutlin 3 via CASC2/miR-367/F-box and WD repeat domain containing 7 (FBXW7) [31]. Chang et al. reported that lncRNA X-inactive specific transcript (XIST) regulated phosphatase and tensin homolog gene (PTEN) expression by sponging miR-181a, and thus contributed to HCC progression [32]. Hence, bioinformatics analysis by Starbase 2.0 was performed to search for potential miRNAs that had a chance to interact with DBH-AS1. Among candidate targets, miR-138 was selected by virtue of its vital roles in cancers including HCC. miR-138, a family of miRNA precursors, has been demonstrated to be frequently downregulated and serve as a tumor suppressor in several tumors, such as larynx cancer [33], non-small cell lung cancer [34], and colorectal cancer [35]. Moreover, enforced expression of miR-138 inhibited cell proliferation and invasion by targeting SOX9 in HCC [18]. Also, Wang et al. revealed that miR-138 overexpression inhibited cell proliferation and migration in HCC [36]. Additionally, some studies showed that miR-138 repressed cell proliferation by targeting cyclin D3 and Sirt1 in HCC [19,20]. Our study further confirmed that DBH-AS1 could function as a ceRNA of miR-138, resulting in the downregulation of miR-138 level in HCC. Functional analyses showed that miR-138 overexpression inhibited proliferation and induced apoptosis in HCC cells, in accordance with the previous studies [[18], [19], [20]]. Furthermore, DBH-AS1 overexpression reversed miR-138-mediated anti-proliferation and pro-apoptosis effects in HCC cells. The FAK/Src pathway is known to be essential for the formation of focal adhesion, cell motility and invasion [37]. FAK/Src signaling was activated and associated with tumor progression in a variety of human malignancies including HCC [38,39]. For instance, calpain small subunit 1 (Capn4) contributed to HCC growth and metastasis via activation of FAK/Src pathway [40]. Scavenger receptor class A, member 5 (SCARA5) silencing contributed to tumorigenesis and metastasis of HCC via activation of FAK signaling pathway [41]. Our study demonstrated that miR-138 overexpression inhibited the phosphorylation of FAK, Src and ERK, indicating the inactivation of miR-138 on FAK/Src/ERK pathway in HCC cells. In line with our results, miR-138 was previously documented to give rise to a decrease in cell motility, invasion colony and stress fiber formation through downregulation of FAK, Src and Erk1/2 in head and neck squamous cell carcinoma [26]. More interestingly, DBH-AS1 overturned the inhibitory effect of miR-138 on FAK/Src pathway in HCC cells. Subsequent transplant tumor experiments verified that DBH-AS1 overexpression accelerated tumor growth, suppressed miR-138 expression and stimulated FAK/Src/ERK pathway, while these effects were substantially undermined after injection with miR-138 mimics. All these data made us draw a conclusion that DBH-AS1 acted as an endogenous sponge of miR-138, thereby activating FAK/Src/ERK pathway and facilitating HCC progression. Moreover, many targets of miR-138 have been reported in cancers [42]. Additionally, Islam et al. pointed out that RhoC as a downstream target of miR-138 could activate FAK/Src/ERK signaling in head and neck squamous cell carcinoma [26]. Hence, in the following explorations, we will proceed to search for the direct targets of miR-138 that activates FAK/Src/ERK signaling.
    Conclusion
    Competing interests
    Acknowledgement
    Main Text Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that integrates signals downstream of growth factor and adhesion receptors. Upon integrin-mediated cell adhesion to the extracellular matrix, FAK localizes into adhesion structures, called focal adhesions (FAs), which form at the cytoplasmic side of the plasma membrane at activated integrin receptor sites. In nascent FAs, FAK plays a crucial skeletal role forming a compact first layer on the plasma membrane and recruiting several other FA proteins. Some FA proteins attach to the actin cytoskeleton, allowing tensile forces to build up by contracting actomyosin fibers. The stretching forces activate several FA proteins, resulting in maturation of FAs (Figure 1). This process is enhanced under external mechanical forces, such as stretching or shear forces, and when cells are grown on stiffer matrices, such as fibrotic tissues. FAs are indeed the sites in which such mechanical signals are translated into biochemical signals. FAK is thought to be one of the crucial tension sensors in FAs, as indicated by the fact that FAK is required for cells to sense stiff substrates and migrate toward them. FAK is important not only in early buildup of FAs but in turning over mature FAs, and thus regulating FA buildup at the cell front and turnover at the rear in migrating cells. This dynamic behavior of FA proteins ensures a constant partition of FA proteins between the FA-bound and cytosolic-diffused state (Figure 1). Because FAK has an active nuclear import signal, it can also enter the nucleus. Whether there are active mechanisms shuttling FAK to the nucleus or whether certain cellular states increase the capacity of FAK interactors in the nucleus to retain FAK is currently unknown. Interestingly, one stimulus resulting in increased FAK levels in the nucleus is mechanical force. Other reported stimuli are oxidative stress (such as H2O2 treatment) and FAK inhibition. The nuclear localization of FAK was relatively recently discovered, and the first evidence that FAK has important roles in the nucleus was provided by Lim et al. (2008). Since then several specific examples have shown that FAK can modulate the activity of transcription factors, by inducing their ubiquitination and degradation, as shown for p53 and GATA4 (Lim et al., 2008, Lim et al., 2012), by binding and inhibiting the MBD2 chromatin remodeling factor (Luo et al., 2009), or by acting as a direct transcriptional enhancer, for example for TFIID (Serrels et al., 2015).