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  • Sorafenib Importantly our in vivo data fit to the


    Importantly, our in vivo data fit to the in vitro data, further confirming the synergistic effect of XJD and gefitinib on the inhibition of lung cancer and the regulation of SP1, HOTAIR, and EP4 Sorafenib levels. The doses of XJD used were based on our previous in vivo study (Zhao et al., 2016). We believed that more experiments are needed to confirm this. Moreover, further studies are required to confirm the combination effect on p-ERK pathway and elucidate the role of EP4. Our current study utilized both in vitro and in vivo approaches and revealed a novel molecular mechanism by which XJD sensitized the anti-tumor effect of gefitinib in lung cancer cells. Nevertheless, the details of the mechanism of synergy of XJD and gefitinib in suppressing cancer growth required to be elucidated in the future.
    Conclusion Collectively, these results show that XJD inhibits NSCLC cell growth via ERK1/2-mediated reciprocal repression of the expressions of lncRNA HOTAIR and SP1 protein levels followed by reducing EP4 gene expression. There is a synergy of XJD and gefitinib in this process (Fig. 8G). This study unveils an additional novel molecular mechanism by which XJD together with gefitinib controls growth of NSCLC cells.
    Conflicts of interest
    Authors’ contribution
    Acknowledgments We are grateful to Dr. Thomas E Eling (NIEHS, USA) for providing the EP4 promoter constructs. This work was supported in part by grants from the National Nature Scientific Foundation of China (Nos. 81403216, 81703551 and 81871863), the Major Program of National Natural Science Foundation of Guangdong (No. 2018B030311061), the Science and Technology Program of Guangzhou (No. 201607010385), Science and Technology Planning Project of Guangdong Province (No. 2017B030314166), the Discipline of Integrated Chinese and Western Medicine in Guangzhou University of Chinese Medicine (No. A1-Af-D018161Z1513), and the Specific Research Fund for TCM Science and Technology of Guangdong Provincial Hospital of Chinese Medicine (No. YN2015MS19).
    Introduction Autosomal-dominant polycystic kidney disease (ADPKD) is a widespread genetic disease that affects 600,000 Americans and 12.5 million people worldwide and accounts for 5% of kidney dialysis and transplant patients ( This disease is characterized by the formation of multiple fluid-filled renal cysts as a result of mutations in the PKD1 or PKD2 genes [1]. The loss of function of PKD1 or other cystic genes acts conjunctly with cAMP signaling to induce epithelial tubular cells to form cysts [2], [3]. Cystogenesis occurs by mechanisms that involve the control of morphogenesis, cellular growth, proliferation differentiation apoptosis, Sorafenib and fluid secretion [4]. We have demonstrated that prostaglandin E2 (PGE2) stimulates cAMP formation and cyst formation in human ADPKD cells [5]. PGE2 binds to 4 cognate receptors (EP1-4) with high affinity and PGD2 and PGF2a receptors with low affinity [6]. EP2 and EP4 receptors are known to activate Gs leading to the stimulation of cAMP formation [7]. From our earlier studies performed in isolated human ADPKD renal epithelial cells, the effect of PGE2 appears to be mediated by EP2 receptors [5], suggesting the therapeutic potential of EP2 receptor antagonists in the treatment of cystogenesis in ADPKD. The development of novel therapies for ADPKD or other renal cystic diseases requires a cell system that is easily available and can be manipulated for the purpose of screening and modulating the biological activity of the disease. Indeed as many studies have also employed mouse models to underwrite confidence in rationale for new approaches in ADPKD [8], we wanted to confirm the suitability of one of these systems for efficacy testing with specific PGE2 receptor antagonists. We selected the mouse IMCD-3 cell line as these cells have been shown to form tubules or cysts in 3D matrices, dependent on presence of extracellular factors [9].