The Role Of Transcription Factor FOXM1in Gastric Cancer Metastasis

BackgroundThe global incidence and mortality of gastric cancer remain highly in recent years. Gastriccancer is also the most common gastrointestinal malignancy in China. The early diagnosisrate of gastric cancer is very low; most patients were detected in the late stage. Earlymetastasis may lead to a variety of treatment methods cannot work and is the leadingcause of death in gastric cancer patients. Therefore, study the molecular mechanism ofgastric cancer metastasis and find effective therapeutic targets has important clinicalsignificance.The activation of transcription factors plays an important role in tumor metastasis;however, the detail molecular mechanism still remains unknown. Recent studies haveshown that members of the FOX family transcription factors (FOXA2, FOXO3a, FOXM1,FOXP3, FOXQ1, et al,) participated in a variety of malignant phenotypes of cancer, suchas malignant proliferation, anti-apoptosis, anti-senescence, angiogenesis, invasion,metastasis and immune escape. FOX family transcription factor proteins play an important role in tumor initiation and progression, and also involved in tumor metastasis. Ourprevious studies have shown that FOXM1played an important role in HCC metastasis, sowe need further research to find whether FOXM1also plays a role in gastric cancermetastasis.MethodsWe used western blot to detect FOXM1expression in different gastric cancer cell lines,immortalized gastric epithelial cells, the high and low invasive gastric cancer cell sublines.The high (MKN28-M) and low (MKN28-NM) invasive gastric cancer cell sublines wereestablished in our laboratory previously. We down-regulated FOXM1expression in highinvasive cell line MKN28-M and up-regulated FOXM1expression in low invasive cellline MKN28-NM by lentivirus infection. And western blot was used to verify theefficiency of virus infection.In vitro, we used the wound healing experiment, high content system cell motilityexperiment, transwell migration and invasion experiment to detect if the migration andinvasion ability of high and low invasive cells was changed after lentivirus infection.In vivo, we used the nude mice tail vein injection model, the small animal in vivo livingimaging system and lung HE staining to detect if the metastasis ability of high and lowinvasive cells was changed after lentivirus infection.ResultsThe expression of FOXM1was significantly lower in immortalized gastric epithelial cellsthan in several gastric cancer cell lines. The FOXM1expression in high invasive gastriccancer cell was significantly higher than in low invasive cell lines.Western blot confirmed the lentivirus infection efficiency after down-regulating FOXM1expression in high invasive cell line MKN28-M. In vitro, the wound healing experiment,high content system cell motility experiment and transwell migration and invasionexperiment found that the migration and invasion ability of high invasive cells wassignificantly weakened compared with the control cells after lentivirus infection. In vivo, the living image and lung HE staining results shown that the metastasis ability ofhigh invasive MKN28-M cells after down-regulating FOXM1expression wassignificantly reduced compared with the control cells.We up-regulated FOXM1expression in low invasive cell line MKN28-NM by lentivirusinfection. Western blot experiment confirmed the infection efficiency. In vitro, the woundhealing experiment, high content system cell motility experiment and transwell migrationand invasion experiment found that the migration and invasion ability of low invasivecells was significantly increased compared with the control cells after lentivirus infection.In vivo, the living image and lung HE staining results shown that the metastasis ability oflow invasive MKN28-NM cells after up-regulating FOXM1expression was significantlyenhanced compared with the control cells.ConclusionsThe higher expression of transcription factor FOXM1in different gastric cancer cell linesand high invasive cell lines than in immortalized gastric epithelial cells and low invasivecell lines indicated that FOXM1may take part in gastric cancer metastasis and play animportant role in this process.In vitro and in vivo experiments confirmed that the metastasis ability of high invasiveMKN28-M cells was significantly impaired after down-regulating FOXM1expression.This indicated that inhibiting FOXM1expression may inhibit the metastasis ability ofgastric cancer cells.After up-regulating FOXM1expression in low invasive MKN28-NM cells, in vitro and invivo experiments confirmed that the metastasis ability was significantly improved. Thisindicated that up-regulating FOXM1expression may enhance the metastasis ability ofgastric cancer cells.All above results together indicated that FOXM1may play an important role in promotinggastric cancer metastasis. FOXM1may be a potential target of gastric cancer treatment.