| Malignant tumors are a major disease that damages human health in the world today and have always been a hot spot in medical research.Among the malignant tumors that threaten human health,lung cancer ranks first.Worldwide,the number of deaths due to lung cancer is more than one million each year,exceeding the sum of colon cancer,breast cancer and prostate cancer.In January 2019,China Cancer Center released Chinese Malignant Cancer Epidemic Analysis in 2015,stating that the new cases of lung cancer were about 800,000 annually.Despite great efforts have been made in diagnosis and treatment,50% of non-small cell lung cancer patients were diagnosed with distal metastasis,involving brain,bone,liver,adrenal gland,skin and eyes.Existing treatment for patients with lung cancer include surgery,radiation therapy,chemotherapy,molecular targeting treatment and immunotherapy.Surgery is in vain when patients are diagnosed with late stage.Besides,radiation therapy,chemotherapy and molecular targeted therapy are often accompanied with a variety of adverse reactions and therapy resistance,whose improvement in survival were limited.In the case of distant metastasis,the prognosis will be poor and median survival may be less than one year.There's usually no cure for metastatic lung cancer.Solving the dilemma of metastatic lung cancer is the key to improve the quality of life and reduce the death rate of patients.There have been many anti-cancer drugs derived from natural plants,such as paclitaxel and camptothecin,have exerted significant therapeutic effects on lung cancer.However,with the continuous reduction of terrestrial biological resources,scientists have gradually turned their research direction to marine organisms,among which the marine algae have exhibited broad application prospects,providing rich resources of anti-cancer moleculars.Fucoxanthin(FX)and eckol(EC)are two bioactive compounds extracted from Laminaria japonica.It has been reported that FX and EC had anti-tumor activity and may be potential tumor treatment drugs.As yet,there has no study about the effects of FX or EC on the migration and invasion of lung cancer cells.Therefore,this study investigated the influences of FX and EC on the metastatic behavior of lung cancer cells both in vitro and in vivo,especially invasion and migration,and revealed the related mechanisms.Objectives: To investigate the effects of FX and EC extracted from Laminaria japonica on the migration and invasion of lung cancer cells both in vitro and in vivo,and explore the molecular mechanisms.Methods: Human lung cancer cells were cultured in vitro,CCK-8 assay was conducted to examine the cell viability.Wound healing assay,the transwell migration and invasion assays were performed to assess the cell migration and invasion ability.A comparative quantitative proteomics analysis was performed in lung cancer A549 cells to revealed differentially expressed proteins after FX or EC treatment,especially the signal pathways related to metastasis.The corresponding expressions of mRNA and protein were detected by RT-PCR and Western Blotting.Nude mice model of metastatic lung cancer was established to investigate the effect of drugs on the metastasis of lung cancer A549 cells.Results: FX and EC decreased the viability of human lung cancer cell lines,A549,H1299 and H446,in a time dose-dependent manner.FX and EC could significantly inhibit the invasion and migration of human lung cancer cell lines,A549,H1299 and H446.Proteomics analysis showed that 256 differential proteins were screened in the FX group,of which 131 proteins were upregulated(FX/Control>1.50)and 125 proteins were downregulated(FX/Control<0.67);217 differential proteins were screened in the EC group,of which 118 proteins were upregulated(FX/Control>1.50)and 99 proteins were downregulated(FX/Control<0.67).The expression of TIMP-2 protein associated with invasion and migration of tumor cells was significantly upregulated.Bioinformatics analysis revealed that these differential proteins were closely related to cell proliferation,apoptosis,RNA transcription,protein translation and modification,regulation of metalloenzyme activity,angiogenesis,and cell movement.Further discovery by RT-PCR and Western Blotting,FX and EC regulated the expressions of EMT-related factors(Snail,Twist,MMP-2,Fibronectin,N-cadherin and TIMP-2),And this may related to the drugs regulation of PI3K/Akt/NF-?B signaling pathway.After continuous intragastric administration of FX and EC,they all showed higher safety than cisplatin.Compared with the control group,the number of metastatic nodules was significantly reduced Conclusion: FX and EC extracted from Laminaria japonica inhibit human lung cancer cell metastasis both in vitro and in vivo.The mechanism may involve the regulation of PI3K/Akt/NF-?B signaling pathway and the inhibition of EMT. |
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