Abstract Non-small cell lung cancer (NSCLC) accounts for more than 85% of lung cancer, with high morbidity and mortality. Studies have shown that microRNA can specifically inhibit the progression of NSCLC. MiR-224-5p can regulate tumor progression in many cancers, but its function and mechanism in NSCLC aren’t clear. In this study, we found that the expression of miR-224-5p was reduced in NSCLC tissue and cells than normal lung tissue and cells. At the same time, miR-224-5p negatively regulates the proliferation and migration of NSCLC cells. Inhibition of miR-224-5p expression in A549 cells could promote cell proliferation, invasion, migration and VM formation in vitro and tumor growth and lung metastasis in vivo, while over expression of miR-224-5p in H226 cells reversed the effect. Besides, we predicted target gene and found that IL6ST is a potential target gene of miR-224-5p. The expression of miR-224-5p is negatively correlated with IL6ST and activation of JAK2/STAT3 pathway. Over expression of IL6ST reversed the effects of miR-224-5p on migration, invasion and activation of JAK2/STAT3 pathway in H226 cells. In conclusion, this study revealed that miR-224-5p can inhibit the proliferation and invasion of NSCLC by targeting inhibition of IL6ST gene transcriptional and inactivation of JAK2/STAT3 signal pathway.

Background and Purpose Hepatocellular carcinoma has high ability of vascular invasion and metastasis. Vasculogenic mimicry (VM) is closely related to the metastasis and recurrence of hepatocellular carcinoma (HCC). According to previous research, Chloranthus henryi has anti-tumor effect, but its molecular mechanism in the treatment of HCC has not yet been stated. In our study, we aimed to investigate the effect of the extract of Chloranthus henryi in HCC and its target and molecular mechanism. Experimental Approach In this study, we isolated a chalcone compound from Chloranthus henryi, compound 4, identified as flavokawain A (FKA). We determined the anti-HCC effect of FKA by MTT and identified the target of FKA by molecular docking and CETSA. Hepatoma cells proliferation, migration, invasion, and VM formation were examined using EDU, wound healing, transwell, vasculogenic mimicry, and IF. WB, RT-PCR, and cell transfection were used to explore the mechanism of FKA on hepatoma cells. Tissue section staining is mainly used to demonstrate the effect of FKA on HCC in vivo. Key Results We confirmed that FKA can directly interact with CXCL12 and HCC proliferation, migration, invasion, and VM formation were all inhibited through reversing the EMT progress in vitro and in vivo through the PI3K/Akt/NF-κB signaling pathway. Additionally, by overexpressing and knocking down CXCL12, we got the same results. Conclusion and Implications FKA attenuated proliferation, invasion and metastatic and reversed EMT in HCC via PI3K/Akt/HIF-1α/NF-κB/Twist1 pathway by targeting CXCL12. This study proposed that FKA may be a candidate drug and prospective strategy for HCC therapy.

Idiopathic pulmonary fibrosis is a progressive fibrotic lung disease characterized by myofibroblast proliferation and extracellular matrix deposition that has a high mortality rate and limited therapeutic options. Flavokawain A(FKA) is the major component of chalcone in kava extract. FKA has been reported to inhibit TGF-β1-induced cardiomyocyte fibrosis by suppressing ROS production in A7r5 cells, but the role and mechanism of FKA in pulmonary fibrosis are unknown. In this study, we evaluated the effect of FKA on pulmonary fibrosis using an animal model of bleomycin-induced pulmonary fibrosis and showed that FKA alleviated the development of pulmonary fibrosis in a dose-dependent manner and improved lung function as well as collagen deposition and extracellular matrix accumulation in mice. In vitro studies showed that FKA inhibited myofibroblast activation and lung fibrosis progression by inhibiting TGF-β1/Smad signaling in a dose-dependent manner. In addition, we identified CXCL12 as a potential target of FKA through target prediction. Molecular docking, CETSA(cellular thermal displacement assay) and silver staining assays further demonstrated that FKA could interact with CXCL12 and that FKA could inhibit CXCL12 dimerization in vitro. Further analysis revealed that FKA could inhibit fibroblast activation and reduce extracellular matrix (ECM) production and collagen deposition by blocking CXCL12/CXCR4 signaling, and knocking down CXCR4 expression could weaken the inhibitory effect of FKA on CXCL12/CXCR4 signal transduction. In conclusion, our study showed that FKA inhibited CXCL12/CXCR4 signaling by inhibiting CXCL12 dimerization, blocked the CXCL12/CXCR4 signaling pathway and inhibited the TGF-β1-mediated signaling pathway to ameliorate pulmonary fibrosis, and FKA is a promising therapeutic agent for pulmonary fibrosis.

Background: Sanghuangporus vaninii has antioxidant, anti-inflammatory, anti-tumor and other effects. However, the antitumor effects and mechanisms of S.vaninii gainst pancreatic cancer remain unclear. Methods: The antitumor activity of compounds isolated from S. vaninii was evaluated, and cell function experiments, such as wound healing, transwell and 3D culture assays, were conducted after the target cancer species was determined. Transcriptome analysis, Micro-Scale Thermophoresis and western blot were used to verify the targets and signaling pathways. Results: 13 compounds were isolated and identified from S.vanini. Among them, compound 1, the phenylpentane derivative compound, has the strongest inhibitory activity on the pancreatic cancer cells. In vitro, compound 1 inhibited the proliferation, migration, invasion, tube formation and colony formation of PANC-1 cells in a dose-dependent manner. Through transcriptome analysis, the signaling pathways compound 1 targeted were identified as MAPK/PI3K and HIPPO pathways. Western blot and immunofluorescence assay also showed that compound 1 can inhibit the EMT through inactivated HIPPO signaling pathway. By molecular docking and MST assay, we confirmed that compound 1 interacted with EGFR by binding with LYS745/PHE856 of EGFR. After knocking down EGFR, the effect of compound 1 on downstream signaling pathways was weakened, and the functions such as migration and invasion of cancer cells were also decreased. Conclusion: Compound 1, the phenylpentane derivative isolated from S. vaninii, inhibited the malignant process and EMT in PANC-1 cells via MAPK/PI3K and HIPPO signaling pathways by targeting EGFR. These data indicated that compound 1 might be a potential drug candidate for pancreatic cancer treatment.

Pulmonary fibrosis is a chronic interstitial fibrosis lung disease with high mortality, which is often complicated with lung cancer. The incidence of IPF complicated with lung cancer is getting higher and higher. At present, there is no consensus on the management and treatment of pulmonary fibrosis patients with lung cancer. There is an urgent need to develop preclinical drug evaluation methods for IPF with lung cancer and potential therapeutic drugs for IPF with lung cancer. The pathogenic mechanism of IPF is similar to that of lung cancer, and the multi-effect drugs with anticancer and anti-fibrosis will have potential value in the treatment of IPF complicated with lung cancer. In this study, we established an animal model of IPF complicated with lung cancer in situ to evaluate the therapeutic effect of the antiangiogenic drug anlotinib. The pharmacodynamic results in vivo showed that anlotinib could significantly improve the lung function of IPF-LC mice, reduce the content of collagen in lung tissue, increase the survival rate of mice, and inhibit the growth of lung tumor in mice. The results of Western blot and immunohistochemical analysis of lung tissue showed that anlotinib significantly inhibited the expression of fibrosis marker protein α-SMA, Collagen I and Fibronectin and tumor proliferation marker protein PCNA in mouse lung tissue, and down-regulated the content of serum tumor marker CEA. Through transcriptome analysis, we found that anlotinib regulates MAPK signal pathway, PARP signal pathway and coagulation cascade signal pathway in lung cancer and pulmonary fibrosis, which all play an important role in lung cancer and pulmonary fibrosis. In addition, there is crosstalk between the signal pathway participated by the target of anlotinib and MAPK, JAK/STAT and mTOR signal pathway. In summary, anlotinib will be a candidate for IPF-LC treatment.