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@#[摘 要] 晚期结直肠癌患者很难从手术和放化疗等传统治疗中获益，从结直肠癌发生发展的分子机制入手探索新的治疗靶点 和方法意义重大。叉头框M1(forkhead box M1，FOXM1)转录因子的异常表达与结直肠癌的发生进展密切相关，异常表达的 FOXM1可通过促进上皮-间充质转化、肿瘤血管生成、调节肿瘤干细胞特性、信号转导通路等影响结直肠癌细胞的增殖、侵袭、 转 移和放化疗抵抗。本文主要就FOXM1在结直肠癌中的作用及其作用机制的最新研究进展作一综述，以期为临床结直肠癌的治 疗提供新的理论依据和治疗靶标。
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@#【Objective】To investigate whether bone marrow mesenchymal stem cells（BMSC）over-expressing FoxM1genecanattenuatelipopolysaccharide（LPS）-inducedapoptosisofalveolarepithelialcells，andexploreitspossi⁃ blemechanism.【Methods】SDratBMSCwereisolatedandculturedbywholebonemarrowadherencemethod.FoxM1 genewasoverexpressedinBMSCbylentiviraltransfection.TheexpressionofthetargetgeneFoxM1wasverifiedbyWestern blot.ApoptosisofA549cellswasmeasuredbyTUNELandflowcytometry.Andthemulti-factorlevelofsupernatantin BMSC-A549co-culturesystemwasdetectedbyMilliplexmethod.【Results】TUNELandflowcytometryconfirmedthat theapoptosisrateofA549inducedbyLPSdecreasedafterco-culturewithBMSCoverexpressingFoxM1，andthediffer⁃ encewasstatisticallysignificant（P <0.05）.MilliplexassayshowedthatthelevelsofIL-13，IL-21，IL-23，MIP-1a， MIP-1bandinBMSCoverexpressing FoxM1 geneandA549co-culturesystemweresignificantlyincreased，whilethe MIP-3alevelissignificantlyreduced.【Conclusion】BMSCoverexpressingFoxM1genecanattenuateLPS-inducedapop⁃ tosisofalveolarepithelialcells.BMSCmayplayananti-apoptoticrolebychangingthelevelsofinflammation-related cytokinesreleasedbyA549cells.
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Purpose Analysis of correlation between FOXM1 gene expression levels and clinicopathological features and prognosis of patients with esophageal squamous cancer (ESC). The effect of down-regulation of FOXM1 expression on the proliferation of human ESC cell line KYSE-30 was also inves-tigated. Methods Quantitative real-time PCR (qRT-PCR) and immunohistochemistry ( IHC) methods were used to detect the expression of FOXM1 in ESC tissues and non-cancer tissues in mRNA and protein level. The expression of FOXM1 was down-regulated by RNA interference (RNAi) technique, and the pro-liferation activity of KYSE-30 cells was detected by CCK-8 as-say. Results Compared with the corresponding non-cancer tis-sues, the expression of FOXM1 was significant higher in ESC tis-sues(P＜0. 01). Meanwhile, the expression levels of FOXM1 in poorly differentiated esophageal carcinoma was higher than that in well-differentiated ESC group ( P ＜0. 01 ). The expression of FOXM1 was significantly correlated with poor tumor differentia-tion (P＜0. 001), lymphatic metastasis (P=0. 000), advanced stage (P=0. 004) of ESC patients after surgical resection. High FOXM1 expression was related to shorter overall survival ( OS) (P＜0. 001). After down-regulating FOXM1 expression in KYSE-30 cells, cell proliferation rate was inhibited (P＜0. 01). Conclusion FOXM1 expression is up-regulated in ESC and is closely related to the degree of differentiation, lymph node me-tastasis, clinical stage and prognosis of ESC. FOXM1 may be participated in regulating the proliferation of human esophageal carcinoma cell line KYSE-30.
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Purpose To investigate the expression of forkhead box M1 (FOXM1) in human colorectal cancer(CRC) tissues,and to analyze the correlation between its expression and clinicopathological parameters and prognosis of CRC.Methods The expression of FOXM1 was examined in 297 cases of CRC tissues and 80 cases of normal peritumoral tissues by immunohistochemistry of SP.Western blot was used to detect the expression of FOXM1 in 20 cases of fresh CRC tissues and the corresponding normal peritumoral tissues.Results The expression of FOXM1 was significantly higher in CRC tissues (60.6％) compared with normal peritumoral tissues (17.50％,P ＜ 0.01).The positive expression of FOXM1 was related to the depth of invasion,lymph node metastasis,intravascular cancer embolus,distant metastasis and TNM stage (P ＜ 0.05).However,there was no correlation with age,sex,tumor location,tumor size,tumor differentiation degree,CEA and CA199 (P ＞0.05).The relative expression levels of FOXM1 protein was also significantly higher in CRC tissues (0.855 ± 0.063) compared with corresponding normal peritumoral tissues (0.150 ± 0.041,P ＜0.01).The 3-year overall survival of CRC patients with FOXM1 expression was significantly lower than that of patients without FOXM1 expression (P＜0.01),and FOXM1 is an independent prognostic factor for CRC.Conclusion The overexpression of FOXM1 protein in CRC tissues correlate with the clinicopathological characteristics and prognosis.FOXM1 may play an important role in the occurrence and metastasis of CRC,and it may be a new tumor marker and potential therapeutic target for CRC.
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Purpose To investigate whether FoxM1 participate in inhibitory effect of cisplatin (CDP) in resistant osteosarcoma cell lines by down-regulation of Rad51.Methods The resistant osteosarcoma cell lines were induced by gradually increasing dose intermittent action,and were named MG-63/R and HOS-MNNG/R respectively.The mRNA and protein level of FoxMl and Rad51 were detected by qRT-PCR and Western blot analysis in resistant cells and parental cells.The mRNA and protein level of FoxM1 and Rad51 were detected by qRT-PCR and Western blot analysis in resistant cells after treatment of 4 μmol/L Thiostrepton.The effect of single or combined treated of 4 tμmol/L Thiostrepton or 2 tμg/mL CDP on the rate of cell proliferation in resistant cells was examed by cell counting.Results Resistant osteosarcoma cell lines MG-63/R and HOSMNNG/R were established and stablely growthed in the concentration of 2 μg/mL CDP,and the resistance index was 30.52 and 37.87 respectively (severe CDP resistance).The mRNA and protein level of FoxM1 and Rad51 were significantly increaced in resistant cells compared with parental cells.The proliferation rate of resistant cells in conbination of 4 μmol/L Thiostrepton and 2 μg/mL CDP treated group was significantly lower than these two drugs single treated group.The level of mRNA and protein of FoxM1 and Rad51 were significantly decreased after 4 μmol/L Thiostrepton treatment in CDP resistant cells.Conclusion The results suggest that FoxM1 and Rad51 may participate in the resistant osteosarcoma cells to CDP.FoxM1 inhibitor Thiostrepton may strengthen the inhibitory effect of CDP in the resistant cells by down-regulation of Rad51.
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Objective To explore the expression of FOXM1 in non-small cell lung cancer(NSCLC) and the relationship between FOXM1 expression and the clinical pathological factors,clinical response to target-therapy in NSCLC remained unknown.Methods A total of 80 NSCLC patients were recruited into this study,FOXM1 expression was assessed by immunohistochemistry and analyzed with the clinical pathological factors and clinical response to target-therapy.Results The positive rate of FOXM1 expression was 41.25%.The positive expression of FOXM1 had no significant difference in patients with different age,gender,cancer staging,smoking history(P>0.05),but had significant difference in patients with different degree of differentiation,lymph node metastasis(P<0.05).Survival time in patients with positive FOXM1 expression was significant shorter than that with negative FOXM1 expression(P<0.05).Conclusion The expression of FOXM1 closely correlated with patients histological differentiation,lymph node metastasis,progress-free survival time in patients with positive FOXM1 expression was significantly shorter than those with negative FOXM1 expression.
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Objective To verify whether miR-498 can inhibit A549 cell migration and invasion by down-regulating FOXM1.Methods miR-498 mimic and miR-NC were transfected into A549 cells.Wound healing and Transwell method were employed to test the migratory ability and invasion ability of A549 cells;Western blot was used to detect the expressions of COL1A1,COL1A5 and FOXM1 in A549 cells.Luciferase assay was used to confirm whether FOXM1 is the target gene of miR-498.Results Compared with those in the control group,the expressions of COL1A1,COL1A5 and FOXM1 were decreased,and the migration and invasion abilities of A549 cells were decreased in the miR-498 group (both P<0 .01 ).The luciferase activity of the FOXM1-3′-UTR plasmid was significantly suppressed by miR-498 (P<0 .05 );over-expression of FOXM1 could reverse the effect of miR-498 on A549 cells.Conclusion miR-498 inhibits A549 cell migration and invasion by down-regulating FOXM1.
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OBJECTIVE: To investigate the molecular mechanisms of proliferation inhibition and apoptosis induction by sophoridine on cell lines from adenocarcinoma in esophagogastric junction. METHODS: After treatment of OE-19 and SK-GT2 cells with 0-3.0 mg·mL-1 of sophoridine for 24, 48 and 72 h, CCK8 was used to examine the proliferation, flow cytometry was used to examine apoptosis, biochemical assay for intracellular ROS and GSH, real-time PCR and Western blot were used to examine FoxM1 mRNA and protein expression, and dual-luciferase reporter gene assay was used for measurement of the transcriptional activity of FoxM1. RESULTS: Sophoridine could significantly inhibit the proliferation of OE-19 and SK-GT2 cell lines, induces apoptosis and G0/G1 arrest of OE-19 cell lines at the concentration of 0.5-1.0 mg·mL-1. Intracellular ROS increase and GSH decrease were observed as well. Moreover, sophoridine attenuated the expression of FoxM1 through suppression of its transcriptional activity. CONCLUSION: It suggests that sophoridine may inhibit proliferation and induce apoptosis of adenocarcinoma from esophagogastric junction in vitro through down-regulating the expression of FoxM1.
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FoxM1 is a specific transcription factor related to proliferation .Previous studies have found that FoxM1 can enhance the proliferation ,metastasis and invasion of cancer cells ,and play a crucial role in canc-er.Recent studies indicate that the abnormal expression of FoxM 1 plays an important role in breast cancer ,and its overexpression is negatively correlated with the overall survival of patients .For the early diagnosis of breast canc-er,clinical prognosis and study on combination therapy provides a new direction .This article reviews the relation-ship between FoxM1 and breast cancer .
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FOX genes code transcription factors. FOXO3a,FOXM1,FOXP3 are members of FOX genes family,which are associated with leukemia. Phosphorylated FOXO3a which loses the function of suppressing leu-kemia is inactive. Phosphorylated FOXO3a expresses in leukemic cell cytoplasm. FOXM1 is an oncogenesis tran-scription factor. FOXM1 highly expresses in myeloid leukemic cells. Expression of FOXP3 in leukemic cells has diversity. FOXP3 mainly expresses in T cell leukemic cells. These genes abrrant expressions play a key role in leukemia pathogenesis,development,therapy,drug resistance and prognosis.
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FOXM1 is a member of the FOX family of transcription factors and has been confirmed to participate in cell prolifera-tion and cell cycle progress. FOXM1 has been reported to play an important role in more than 20 types of human neoplasms, and its up-regulation promotes tumor cell proliferation, invasion, metastasis, chemotherapy drug resistance, and resistance to apoptosis. In recent years, various studies have shown that FOXM1 also plays an important role in tumor metabolism. The metabolism of cancer cells deter-mines the growth and survival of cancer, and metabolic alteration is a key feature of tumor cells. The connection between metabolic ab-normalities and tumorigenesis has been reported. The O-linkedβ-N-acetylglucosamine transferase regulates the expression of FOXM1, which helps tumor cells survive without damage caused by oxidative stress. This review aims to summarize the known relationships of FOXM1 and tumor cell metabolism, as well as its role in the potential pathways of tumor metabolism.
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Aim To investigate the expression and im-plication of HIF-1α, ROCK-2 , FoxM1 in PC12 cell in-jury induced by lead acetate. Methods PC12 cells were treated with lead acetate at the doses of 100 , 200 and 400 μmol·L-1 . The cell viability was determined by MTT reduction assay and LDH assay, the intracellu-lar production of oxygen species was measured by as-sessing SOD and MDA levels, cell apoptosis was deter-mined by Hoechst 33342 staining, the expressions of HIF-1α, ROCK-2 , FoxM1 , Bcl-2 and Bax were deter-mined by immunoblotting analysis. Results Lead ac-etate induced cell injury in PC12 cells in a dose-de-pendent manner, and it potentiated oxygen radical pro-duction and cell apoptosis. In addition, lead acetate enhanced HIF-1α and ROCK-2 expressions, increased Bax/Bcl-2 ratio and decreased FoxM1 expression. Conclusion Lead acetate can induce PC12 cell apop-tosis, which may be related with the expressions of HIF-1α, ROCK-2 and FoxM1 . Cellular oxidative stress may contribute to the injury as well.
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[Abstract ] Forkhead box(Fox) M1, as a member of the Fox transcription factor family, overexpresses in many kinds of canc-ers and is related to a variety of oncogenic signaling pathways.It plays an important role in the occurrence, progression and metastasis of cancer.FoxM1 has been a new target for cancer therapy research.
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Objective:To investigate the effects of the miR-149 on the growth and invasion of prostate carcinoma cells. Meth-ods:Real-time fluorescence quantitative polymerase chain reaction was performed to detect the expression of miR-149 on prostate car-cinoma tissues and paraneoplastic tissues. The PC3 and DU145 cells were transfected with miR-149 mimics and negative controls. The cell growth and invasion abilities were tested in terms of colony formation and via Transwell invasion assay. The cells were transfected with the siRNA of the target gene FOXM1 and siRNA control. Western blot was used to detect the expression of FOXM1. The cell colo-ny formation and invasion ability were also detected. Results:Compared with the paraneoplastic tissues, miR-149 was down-regulated in the prostate carcinoma tissues (P<0.01), and the FOXM1 mRNA was highly expressed (P<0.01). PC3 and DU145 cells with miR-149 mimics had only a few colonies and invading cells (P<0.01). Moreover, PC3 (P<0.01) and DU145 (P<0.05) with miR-149 mimics had a low protein level of FOXM1. The FOXM1 expression was knocked down by the siRNA of FOXM1 in the PC3 and the DU145 cells (P<0.01). The knocking down of FOXM1 resulted in an inhibition of the cell colony formation and invasion abilities (P<0.01). Conclusion:The miR-149 inhibits prostate carcinoma cell growth and invasion by suppressing the FOXM1. Our data suggest that miR-149 may function as an effective tool for the molecular treatment of prostate cancer.
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Objective The invasion and metastasis of colon cancer often leads to treatment failure and mortality in patients . Our research is to investigate the influence of FoxM 1 to malignant human colon cancer line . Methods In two human colon cancer lines, the protein and mRNA expression levels of FoxM 1 were analyzed with the application of RT-PCR and Western blot , from which high-expressed HT-29 and low-expressed HCT-116 were determined.The expression of FoxM1 was down-regulated by RNA interfering in HT-29 and up-regulated by constructing overexpression transgenic line in HCT-116.The proliferation of the above cells was assayed by healing method;while the metastasis and invasion ability were examined by Transwell chamber assay . Results Two colon cancer lines were selected with high-expression or low-expression of FoxM1 separately named HT-29 and HCT-116.Application of PEX-2-FoxM1 raised after HCT-116 cells express FoxM1, cell scratches in HCT-116 experimetal group ([70.92 ±1.48]%) compared with HCT-116 control group([16.92 ±4.05]%)and HCT-116 blank control group([16.66 ±2.63]%) will markedly enhance its capabil-ity of healing (P<0.05), Transwell Chambers in membrane cells in HCT-116 experimetal group (186.0 ±6.8) compared with HCT-116 control group(42.0 ±2.0) and HCT-116 blank control grou (37.0 ± 2.2)was increased (P<0.05).On the other hand, the applied pG-PH-shFoxM1 can reduce FoxM1 expression in HT-29 cell, cell scrat-ches healing ability in HT-29 experimetal group ( [ 10 .37 ± 3.86]%) compared with HT-29 control group([34.63 ±2.35]%)and HT-29 blank control group([67.36 ±2.61]%) decreased significantly (P<0.05), Transwell Chambers in membrane cells in HT-29 experimetal group (53.0 ±1.8)compared with HT-29 control group(95.0 ±2.2)and HT-29 blank control grou(118.0 ±4.0) was also reduced (P<0.05). Conclusion The expression of FoxM1 is in close relation to the invasion and metastasis of CRC .The fact that the siRNA interfering FoxM1 could effectively inhibit the proliferation, metastasis and invasion, suggesting FoxM1 could po-tentially be a new molecular target for inhibiting the proliferation of human colon cancer line .
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Objective To detect the expression of FOXM 1 transcription factor in cervical cancer tissues and to evaluate its clini-cal significance .Methods Immunohistochemical staining was employed to detect the expression of both FOXM 1 and Ki-67 in a va-riety of cervical tissues respectively from 38 patients with cervical cancer ,22 with cervical intraepithelial neoplasia (ranging from CINⅠ to CIN Ⅲ) and 17 with normal cervical epithelium .Results Abnormal expression rate of FOXM 1 was respectively 5 .88% , 63 .6% and 92 .1% in normal cervix ,CIN and cervical cancer ;Deregulated FOXM1 expression in cervical cancer tissues was signifi-cantly correlated with patients’ pathological differentiation ,clinical stage ,post-operational recurrence and Ki-67 expression level . Conclusion FOXM1 expression may be correlated with the deregulated proliferation ,malignant progression ,staging and prognosis in cervical cancer .
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Objective To study the expression and clinical significance of FoxM1 and Cep55 protein in basal-like breast carcinoma (BLBC).Methods The expression of FoxM1 and Cep55 protein in 66 cases of BLBC,70 cases of non-BLBC and 66 cases of normal adjacent breast tissue were detected by immunohistochemistry.Their relationship with the clinical pathological factors was analyzed.Results The positive rate of FoxM1 protein in BLBC,non-BLBC and normal adjacent breast tissue was 77.3％ (51/66),60.0％(42/70) and 13.6％(9/66),Cep55 protein was 74.2％(49/66),57.1％(40/70) and 16.7％(11/66),respectively.BLBC and non-BLBC tissue were higher than normal adjacent breast tissue,and BLBC tissue was higher than non-BLBC,there was significant difference (P ＜0.05).In BLBC tissue,the positive expression of FoxM1 and Cep55 protein correlated with lymph nodes metastasis and TNM staging (P ＜0.05),while did not correlate with age,menopause,tumor size (P ＞ 0.05).There was direct correlation between the positive expression of FoxM1 and Cep55 protein (r =0.259,P ＜ 0.05).Conclusion FoxM1 and Cep55 protein may play an important role in the carcinogenesis and development of BLBC,and both of them have the synergistic effect.
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Objective To investigate the expression of forkhead box Ml (FoxMl) transcription factor and cyclooxygenase- 2 (COX-2) in nasopharyngeal carcinoma (NPC) tissues, and to discuss the related clinicopathological implications. Methods Immunohistochemistry method wasused to examine the expression of FoxM1 and COX-2 in80 NPC tissues and 40 normal nasopharyngeal mucosa tissues. The relationship of FoxM1and COX-2expression with the clinicopathological parameters of NPC was analyzed; we also analyzed the correlation between the FoxM1 and COX-2 expression. Results FoxM1 and COX-2 expressions were significantly higher in NPC tissues compared to normal nasopharyngeal mucosa tissues (FoxM1: 68. 8% [55/ 80] vs 2. 5% [1/40]; COX-2: 62. 5% [50/80] vs 5. 0% [2/40]; P<0. 05). The expression of FoxM1 was significantly associated with lymph node metastasis (rs =0. 252, P<0. 05) and clinical stage of NPC (rs = 0. 230, P<0. 05), and expression of COX-2 was also significantly associated with lymph node metastasis (r = 0. 287, P<0. 05) and clinical stage of NPC (r = 0. 239, P<0. 05). Furthermore, a positive correlation was observed between FoxM1 and COX-2 expression (rs = 0. 631, P< 0. 05), indicating a direct or indirect interaction between them. Conclusion Increased expression of FoxM1 and COX-2 in NPC tissues might be associated with the development and progression of NPC.
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PURPOSE: Recently, Forkhead box M1 (FoxM1) was reported to be correlated with lung maturation and expression of surfactant proteins (SPs) in mice models. However, no study has been conducted in rabbit lungs despite their high homology with human lungs. Thus, we attempted to investigate serial changes in the expressions of FoxM1 and SP-A/B throughout lung maturation in rabbit fetuses. MATERIALS AND METHODS: Pregnant New Zealand White rabbits were grouped according to gestational age from 5 days before to 2 days after the day of expected full term delivery (F5, F4, F3, F2, F1, F0, P1, and P2). A total of 64 fetuses were enrolled after Cesarean sections. The expressions of mRNA and proteins of FoxM1 and SP-A/B in fetal lung tissue were tested by quantitative reverse-transcriptase real-time PCR and Western blot. Furthermore, their correlations were analyzed. RESULTS: The mRNA expression of SP-A/B showed an increasing tendency positively correlated with gestational age, while the expression of FoxM1 mRNA and protein decreased from F5 to F0. A significant negative correlation was found between the expression levels of FoxM1 and SP-A/B (SP-A: R=-0.517, p=0.001; SP-B: R=-0.615, p<0.001). CONCLUSION: Preterm rabbits demonstrated high expression of FoxM1 mRNA and protein in the lungs compared to full term rabbits. Also, the expression of SP-A/B was inversely related with serial changes in FoxM1 expression. This is the first report to suggest an association between FoxM1 and expression of SP-A/B and lung maturation in preterm rabbits.