Overexpression of Her-2 upregulates FoxM1 in gastric cancer

  • Authors:
    • Weiwei Qi
    • Xiaoxiao Li
    • Yongchun Zhang
    • Ruyong Yao
    • Wensheng Qiu
    • Dongfang Tang
    • Jun Liang
  • View Affiliations

  • Published online on: April 7, 2014     https://doi.org/10.3892/ijmm.2014.1732
  • Pages: 1531-1538
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Abstract

The transcription factor, forkhead box protein M1 (FoxM1), and the tyrosine kinase receptor, human epidermal growth factor receptor-2 (Her-2), are aberrantly expressed in a number of human malignancies, and are closely associated with the development of cancer. However, their regulatory mechanisms and their involvement in tumor development have not been extensively investigated, particularly in gastric cancer. In the present study, we examined the expression levels of FoxM1 and Her-2 in samples from patients with gastric cancer, as well as gastric cancer cell lines. Their regulatory mechanisms and the connection between them were also explored. We found that FoxM1 and Her-2 expression was markedly higher in the gastric cancer samples, while a strong association was found between them at the mRNA and protein level. When we regulated the levels of Her-2 in the gastric cancer cell lines, the expression of FoxM1 changed accordingly. Following the transfection of Her-2 expression vectors into the gastric cell lines, the luciferase activity of the FoxM1 promoter positively increased along with the concentration of pcDNA3.1-Her-2. However, Her-2-siRNA inverted this variation, which was further confirmed by treatment with the Her-2 inhibitor, trastuzumab, revealing that Her-2 regulates FoxM1 expression at the promoter level in gastric cancer cells. Our results suggest that FoxM1 and Her-2 are important diagnostic markers for gastric cancer. FoxM1 may be a potential cellular target for therapeutic intervention, particularly in gastric cancers resistant to Her-2-targeted therapy.

Introduction

Forkhead box protein M1 (FoxM1) belongs to the forkhead transcription factor family, which shares the same DNA-binding domain, known as the forkhead box or winged helix domain (1). Recent studies indicate that FoxM1, activated by the Ras-MAPK and hedgehog signaling pathways (2,3), plays an important role in the cell cycle by regulating genes essential for DNA synthesis, faithful chromosome regulation and mitosis (4,5). FoxM1 maintains a dynamic balance between proliferation and apoptosis, and its dysfunction may alter the normal process of cell differentiation, eventually leading to carcinogenesis. Previous studies have demonstrated that FoxM1 is overexpressed in gastric cancer and that elevated FoxM1 levels promote tumor progression in glioma cells, breast cancer and lung adenocarcinomas, which correlates closely with a poor outcome (69). Moreover, FoxM1 amplification confers to acquired cisplatin resistance in breast cancer and primary resistance to gefitinib in non-small cell lung cancer (NSCLC) (10,11), which suggests that the inhibition of FoxM1 expression may be a novel therapeutic strategy for gastric cancer. However, in order to acquire a complete understanding of the mechanisms through which FoxM1 is regulated, further investigation is required.

Human epidermal growth factor receptor-2 (Her-2) is a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases (RTKs), involved in the development and progression of various solid tumor types, such as gastric cancer, pulmonary adenocarcinoma, colorectal and breast cancer (6,1214). Her-2 does not bind ligands directly, but can be transactivated by the other EGFRs, leading to an amplification of signal transduction (15). Emerging evidence suggests that EGFR family members, enhanced by ERK1/2 MAP kinase and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB also known as Akt) signaling cascades, are established regulators of cell proliferation and survival, and its aberrant signaling is a common feature of many tumor types (1517). Moreover, the amplification of Her-2 in primary gastric cancer correlates with a poor prognosis and disease progression (18), whilst the Her-2 blocking antibody, trastuzumab (also known as Herceptin), is currently approved for the treatment of Her-2-positive breast cancer (19) and metastatic gastric cancer as a result of the ToGA trial (20). Given the overlapping roles of FoxM1 and Her-2 in cell proliferation, survival and gastric cancer development, as well as their role as therapeutic targets, it can be hypothesized that Her-2 may in part regulate FoxM1 expression in the development of gastric cancer and thereby promote cell cycle progression. In the present study, we aimed to examine this hypothesis by investigating the association between FoxM1 and Her-2 expression in gastric cancer.

Materials and methods

Human tissue specimens and patient population

Gastric cancer tissues were obtained from 103 patients who underwent gastrectomy and D2 lymphadenectomy at the Affiliated Hospital of Qingdao University Medical College (Qingdao, China) from January 2007 to November 2007. A total of 68 adjacent cancer tissues, which were >5 cm away from the edge of the tumor, were randomly selected. All patients met the following criteria: i) tumors were confirmed to be gastric adenocarcinoma histologically; ii) no patient had received pre-operative treatment, such as chemotherapy or radiotherapy. The group of patients consisted of 35 females and 68 males with ages ranging between 33 and 80 years (mean age, 64 years). Clinico-pathological data were obtained from the operative and pathological examination of the patients, and are presented in Table III.

Table III

Association between FoxM1 or Her-2 and clinicopathological characteristics in 103 patients following gastrectomy.

Table III

Association between FoxM1 or Her-2 and clinicopathological characteristics in 103 patients following gastrectomy.

FoxM1Her-2


NegativePositiveP-valueNegativePositiveP-value
Age (years)
 ≤5041311540.598
 >5018687311
Gender
 Male15530.8095990.591
 Female728296
Size (cm)
 ≤515580.75461120.593
 >5723273
Depth of tumor invasion
 T1-27330.4463730.105
 T3-415485112
Lymph node metastatis
 Negative8320.7893640.295
 Positive14495211
Degree of differentiation
 Undifferentiated17580.5966690.372
 Differentiated523226
Venous invasion
 Negative14470.7015470.284
 Positive834348
Neural invasion
 Negative10460.3444790.636
 Positive1235416
TNM staging
 I–II7380.2064230.045a
 III–IV15434612

a P<0.05.

{ label (or @symbol) needed for fn[@id='tfn4-ijmm-33-06-1531'] } FoxM1, forkhead box protein M1; Her-2, human epidermal growth factor receptor-2.

Cell lines and culture conditions

Five gastric cancer cell lines, SGC-7901, AGS, SNU16, MKN-28 and NCI-N87 and 2 normal gastric epithelial cell lines, GES-1 and HFE-145, which have different expression levels of FoxM1 and Her-2, were obtained from the Central Laboratory of the Affiliated Hospital of Qingdao University Medical College. All 7 cell lines were cultured in RPMI-1640, supplemented with 10% FBS (Thermo Scientific, San Jose, CA, USA) and 1% penicillin/streptomycin, and incubated in 5% CO2 at 37°C. The anti-Her-2 tyrosine kinase inhibitor, trastuzumab (Chembest Research Laboratories, Shanghai, China), was dissolved in sterile water and diluted to a final concentration of 3, 5 and 10 μg/ml prior to use, as previously described (21).

Immunohistochemistry (IHC)

The expression of FoxM1 was detected by IHC with 3-μm-thick sections of formalin-fixed and paraffin-embedded blocks. For IHC staining, the tissue sections were dewaxed in xylene and rehydrated gradually with a graded series of ethanol. For antigen retrieval, all the sections were incubated in a microwave oven in citrate buffer solution (pH 6.0) for 20 min. Endogenous peroxidase was inactivated by 0.3% hydrogen peroxide in methanol for 15 min. Subsequently, the tissue slides were incubated with rabbit polyclonal antibody against human FoxM1 (dilution 1:100; Epitomics, Burlingame, CA, USA) and Her-2 (dilution 1:200; Abcam, Cambridge, MA, USA) at 4°C overnight and then the antibody binding sites were visualized with the SP peroxidase detection system. Finally, the sections were incubated in 3,3′-diaminobenzidine tetrahydrochloride for 3–10 min and restained with 0.1% hematoxylin. In each case, the negative control reaction was set with phosphate-buffered saline (PBS), replacing the antibody, while the known positively stained section was used as the positive control. The results of IHC were evaluated by 2 pathologists independently with no knowledge of the clinicopathological characteristics according to the semiquantitative immunoreactivity score (IRS) system suggested by in the study by Remmele and Stegner (22) and the Her-2 test criteria modified in the study by Hofmann et al (23).

Western blot analysis

Whole-cell lysates were prepared from human gastric cell lines which were in the logarithmic growth phase, 48 h after transfection or 72 h following incubation with trastuzumab. The protein concentration was determined using the Beijing Kaiao assay system (Beijing Kaiao Technology Development Co., Ltd., Beijing, China). Total protein was fractionated using sodium dodecyl sulfate polyacrylamide gel electrophoresis and transferred onto polyvinylidene fluoride membranes. Anti-FoxM1 (dilution 1:1,000; Epitomics), anti-Her-2 (dilution 1:2,000; Abcam) and anti-GAPDH (dilution 1:2,000; CWBIO, Beijing, China) rabbit polyclonal antibodies were used as the primary antibodies. The signals were detected using the Vilber enhanced chemiluminescence system (Vilber Lourmat, Marne La Vallée, France) according to the manufacturer’s instructions.

RNA extraction and RT-PCR

Total cellular RNA was extracted from the cell pellets of each cell line using TRIzol reagent, according to the protocol suggested in the study by Okada et al (6). In addition, 70 gastric cancer tissues randomly selected from the 103 patients were used for RNA extraction. For these paraffin-embedded tissues, sufficient sections were prepared, deparaffinized and conventionally re-hydrated in a decreasing alcohol series prior to RNA extraction, as previously described (24). The amount of RNA was determined using the Beijing Kaiao assay system (K5500; Beijing Kaiao Technology Development Co., Ltd.), and then part of the RNA was reverse transcribed using the Reverse Transcription System (Takara Bio, Inc., Dalian, China). Samples were stored at −80°C until use.

The primer sequences for PCR amplification were as follows: FoxM1 sense, 5′-TAT TCA CAG CAT CAT CAC AGC A-3′ and antisense, 5′-GAA GGC TCC TCA ACC TTA ACC T-3′; Her-2 sense, 5′-TCT GCT GGA GGA ATT GGT GT-3′ and antisense, 5′-GAC GCT TGT TCC CAC CTT GA-3′; GAPDH sense, 5′-ACC ACA GTC CTG CAT GCC AC-3′ and antisense, 5′-TCC ACC ACC CTG TTG CTG TA-3′. To ensure experimental accuracy, all reactions were performed in triplicate. The integrity of all the RNA samples was verified by RT-PCR for GAPDH in each sample using a gel imaging system (Vilber Lourmat). The value of FoxM1 expression was divided by that of GAPDH in each sample.

Plasmids and transfection

The human Her-2 expression vector, pcDNA3.1-Her-2, Her-2-siRNA and the human FoxM1 promoter reporter plasmid were obtained from the Central Laboratory of the Affiliated Hospital of Qingdao University Medical College. For transfection, the cells were seeded to a 40–50% confluent state and transfected with pcDNA3.1-Her-2, pcDNA3.1, Her-2-siRNA or non-specific siRNA using Lipofectamine 2000 (Invitrogen, Carlsbad, CA, USA) in accordance with the manufacturer’s instructions. For the human FoxM1 promoter plasmids containing firefly luciferase reporters, an internal control, pMiniTK-RL, which included a full-length Renilla luciferase gene under the control of a minimal thymidine kinase promoter, was co-transfected into the gastric cancer cell lines in triplicate. Twenty-four hours after transfection, the cells were harvested for luciferase assay.

Luciferase reporter assay

For promoter analysis, 24 h after transfection, the cells were collected, washed twice in PBS, and harvested for firefly/Renilla luciferase assays using the Dual-Glo™ Luciferase reporter assay system (Promega, Madison, WI, USA) according to the manufacturer’s instructions. Subsquently, luminescence was read using the Tecan Safire II microplate reader (Tecan, Männedorf, Switzerland).

Statistical analysis

The SPSS 19.0 software package (SPSS Inc., Chicago, IL, USA) was used for the statistical analysis. The χ2 test and the Student’s t-test were performed to determine the difference between the different subgroups. A value of P<0.05 was considered to indicate a statistically significant difference.

Results

Overexpression of FoxM1 and Her-2 expression in both malignant human gastric cell lines and gastric cancer tissues

We initiated our study by investigating the expression level of FoxM1 and Her-2 in benign and malignant human gastric cell lines. Western blot analysis revealed a homogenous FoxM1 expression in the normal gastric epithelial cell lines (GES-1 and HFE-145), whereas the expression levels were more heterogeneous and elevated in the cancerous cell lines (Fig. 1A) (P=0.008). In the malignant human gastric cell lines, only the SGC-7901, NCI-N87 and AGS cells exhibited the expression of Her-2, whereas low expression levels were observed in the non-malignant gastric cell lines, among which, the differences were significant (Fig. 1A) (P<0.001).

In the gastric cancer tissues, FoxM1 was stained positive in the nuclei or cytoplasm of 79% of the cells, while this number was 14% for Her-2 (Fig. 1B). However, much lower levels of FoxM1 and Her-2 expression were observed in the adjacent cancer tissues (11.8 and 1.5%), which demonstrated that the level of FoxM1 and Her-2 expression was significantly higher in the gastric cancer than in the adjacent cancer tissues (Table I) (P<0.001 and P=0.004), indicating that FoxM1 is overexpressed in human gastric cancer.

Table I

Differential FoxM1 and Her-2 expression in human gastric cancer tissues and adjacent cancer tissues.

Table I

Differential FoxM1 and Her-2 expression in human gastric cancer tissues and adjacent cancer tissues.

FoxM1Her-2


VariablePositiveNegativePositiveNegative
Gastric cancer tissues81221588
Paraneoplastic tissues860167
χ281.0758.278
P-value<0.0010.004

[i] FoxM1, forkhead box protein M1; Her-2, human epidermal growth factor receptor-2.

Her-2 expression correlates with FoxM1 expression at the protein and mRNA level

To examine whether FoxM1 expression correlates with Her-2 expression, we analyzed Her-2 and FoxM1 expression in a panel of 5 different malignant gastric cell lines by western blot analysis. Consistent with our hypothesis that Her-2 may partly regulate FoxM1 expression, 3 gastric cancer cell lines positive for Her-2 expression exhibited high levels of FoxM1 protein, whilst one cell line with no Her-2 expression also lacked the expression of FoxM1 (Fig. 1A). Therefore, 4 of the 5 gastric cancer cell lines demonstrated a positive correlation between the levels of Her-2 and FoxM1. One of the cell lines did not exhibit this correlation; in this case, it is possible that other mechanisms may influence the FoxM1 levels more significantly. Moreover, at the transcription level, similar results were obtained by RT-PCR, in which the positive correlation was observed in most of the malignant gastric cell lines (Fig. 2A).

To confirm that the correlation between FoxM1 and Her-2 expression is also valid in tumor tissues, a series of 103 paraffin-embedded gastric cancer samples were immunohistochemically stained for Her-2 and FoxM1. As expected, in the gastric cancer samples, the majority of cells with Her-2 expression were positively stained for FoxM1, whilst the samples devoid of Her-2 staining also lacked FoxM1 expression (Fig. 1B). Statistical analysis revealed that there was a significant and positive correlation between FoxM1 and Her-2 expression (P=0.025) (Table II). Nevertheless, no significant association was observed between the expression of FoxM1 and any clinicopathological characteristics (Table III; P>0.1), whereas the frequency of Her-2-positive cases significantly correlated with the TNM stage (P=0.045). To investigate whether Her-2 overexpression is associated with increased levels of FoxM1 expression at the transcriptional level, we examined FoxM1 mRNA levels by RT-PCR in 70 randomly selected gastric cancer tissues. Consistent with our previous data, the RT-PCR results indicated that when the patient samples were categorized by their Her-2 status, the Her-2-positive samples had a significantly higher expression of FoxM1 at the transcriptional level (Fig. 2B; P=0.007).

Table II

Significant association between the expression of FoxM1 and Her-2 in human gastric cancer tissues (P=0.025).

Table II

Significant association between the expression of FoxM1 and Her-2 in human gastric cancer tissues (P=0.025).

VariableHer-2-negativeHer-2-positiveχ2P-value
FoxM1-negative1575.0470.025
FoxM1-positive738

[i] FoxM1, forkhead box protein M1; Her-2, human epidermal growth factor receptor-2.

Alterations in Her-2 expression modulate FoxM1 expression in gastric cancer cell lines

To determine whether Her-2 regulates FoxM1 expression, different levels of pcDNA3.1-Her-2 or the empty vector were transfected into the SGC-7901, AGS and SNU16 cells. Our results revealed that the FoxM1 expression level was increased following transfection with Her-2 expression vectors, of which the amplification coincided with the levels of Her-2 expression, as shown by western blot analysis (Fig. 3A).

To further validate that Her-2 partly regulates FoxM1, we transfected the SGC-7901 and NCI-N87 cells with Her-2-siRNA or non-specific siRNA. The ablation of Her-2 in the cells resulted in a reduced FoxM1 expression at the protein level (Fig. 3B, top panel). Moreover, when the gastric cell lines, SGC-7901 and NCI-N87, were treated with various concentrations (0, 5 or 10 μg/ml) of anti-trastuzumab (an Her-2 tyrosine kinase inhibitor), similar results were observed, and as the concentration of trastuzumab increased, the expression of FoxM1 was downregulated (Fig. 3B, bottom panel).

Her-2 regulates FoxM1 expression at the promoter level

To investigate whether FoxM1 is a downstream signaling target of Her-2 in gastric cancer, we co-transfected the FoxM1 promoter reporter plasmid with Her-2 overexpression vectors or Her-2-siRNA into the human malignant gastric cell lines. The results of luciferase reporter assays (Fig. 4) revealed that the relative luciferase activity was generally elevated with the increasing pcDNA3.1-Her-2 concentration in the AGS and SGC-7901 cells (Fig. 4A), while Her-2-siRNA inhibited the luciferase activity driven by the FoxM1 promoter in the NCI-N87 and SGC-7901 cells (Fig. 4B), verifying that Her-2 regulates FoxM1 expression at the transcriptional level.

In order to further confirm this result, we then transfected FoxM1 promoter reporter plasmids and trastuzumab into the SGC-7901 and NCI-N87 cells. Twenty-four hours later, the luciferase activity of the promoter reporter construct was observed to be decreased (Fig. 4C), which indicated that trastuzumab induced a reduction in FoxM1 expression and further supports our hypothesis.

Discussion

In the present study, we demonstrate that FoxM1 and Her-2 expression is significantly higher in gastric cancer than in adjacent cancer tissues and gastric cell lines. A strong association was observed between Her-2 and FoxM1 expression at the mRNA and protein level. When we regulated the level of Her-2 in the gastric cancer cell lines, the expression of FoxM1 changed accordingly, indicating that the expression level of FoxM1 was at least partially regulated by Her-2. In order to validate our results, we transfected FoxM1 promoter reporter plasmids and Her-2 expression vectors into malignant human gastric cell lines, where the luciferase activity of the promoter reporter construct increased with the increasing amount of pcDNA3.1-Her-2. Consistently, when Her-2-positive cells were incubated with Her-2-siRNA or the Her-2 inhibitor, trastuzumab, the transfected FoxM1 promoter reporter constructs showed a decrease in promoter activity. Our results demonstrate that FoxM1 and Her-2 are important diagnostic markers for gastric cancer, and that the upregulation of FoxM1 expression is at least partially mediated at the mRNA level through the regulation of the FoxM1 promoter by Her-2.

The Her-2 gene is localized on chromosome 17q and codes for a transmembrane glycoprotein of 185 kDa. Her-2 plays an important role in normal development, differentiation and apoptosis of cells. Her-2 gene amplification has been reported in various types of cancer, including ovarian, lung and breast cancers (13,14,25). It has been reported that Her-2 is overexpressed in 9–38% of patients with gastric cancer (26), and is associated with certain clinicopathological characteristics and a poor survival in univariate analysis, but is not independently correlated with prognosis in multivariate analysis (27,28). However, in the studies by Okada et al (6) and Li et al (29), positive FoxM1 expression was an independent prognostic factor in gastric cancer, but did not correlate with any clinicopathological characteristics; the opposite occurred for Her-2. The results from the present study are in agreement with those of previous studies, as no significant association was found between the expression of FoxM1 and any clinicopathological characteristics, while Her-2 expression only significantly correlated with the TNM stage. Additionally, in agreement with the study by Okada et al (6), our study revealed that FoxM1 was associated with a poor survival, consistent with Her-2. Therefore, these results indicate that these two genes have a similar tendency as regards clinicopathological parameters and survival, suggesting that Her-2 expression may correlate with FoxM1 expression significantly.

Our present data revealed that FoxM1 is associated with Her-2 expression in gastric cancer, and that it is a downstream cellular target of Her-2-dependent signaling, which activates FoxM1 expression at the protein, mRNA and gene promoter levels. It has been reported that FoxM1 overexpression confers resistance to the Her-2 monoclonal antibody, trastuzumab (21); the mechanisms through which Her-2 regulates FoxM1 expression levels may be critical for understanding the mechanisms of FoxM1-mediated acquired resistance to Her-2. Moreover, previous studies have shown that Her-2 and its co-receptor, EGFR, suppress FOXO3a through the PI3K-Akt pathway, while FOXO3a inactivation releases a switch in promoter occupancy from FoxM1, which then modulates the cell cycle through the Cdc25B, CDK1, cyclin B and p27KIP genes (4,5,30,31). The PI3K-Akt-FOXO3a signaling axis may provide the link between Her-2 and FoxM1 expression. Of note, FOXO has been revealed to have opposite effects with FoxM1 on the reaction to a diverse spectrum of anticancer drugs, such as lapatinib and gefitinib (32), and thus it can be concluded that FOXO may be discussed as a novel anticancer agent of Her-2-overexpressing cancers in further investigations.

The ToGA trial (20) led to the conclusion that trastuzumab can be used to treat patients with Her-2 overexpression, and thus the determination of the Her-2 status is a very important step in clinical routine to determine the therapeutic strategy. However, the majority of patients develop resistance to trastuzumab during therapy (33), indicating that the analyses of other potential target molecules in signaling pathways of malignant gastric cells are of great interest and may offer alternative treatment options for patients with resistance to trastuzumab. FoxM1 may be such a candidate molecule. FoxM1 inhibitors have been discussed as novel anticancer therapeutics (3436), which may prove to be a successful tool to sensitize various tumor types to treatment. Bhat et al (34) suggested that Siomycin A and thiostrepton (FoxM1 inhibitors/thiazole antibiotics) may be potentially developed as novel anticancer drugs against human neoplasia (35). Furthermore, Gusarova et al (35) showed that the inhibition of FoxM1 function by a cell-penetrating ARF peptide led to reduced tumor cell proliferation and angiogenesis in hepatocellular carcinoma (36). Nevertheless, this inhibitory effect on FoxM1 has not been analyzed for human gastric cancer thus far. Therefore, further functional studies are required to focus on the function of FoxM1 in Her-2-targeted therapy-resistant gastric cancer.

Although this study provides evidence of the regulation of Her-2 on the FoxM1 gene promoter, accurate binding sites at the gene level were not revealed yet. Moreover, from the differential expression of FoxM1 and Her-2 in gastric cancer tissues and cell lines, we can infer that there are other mechanisms that may also influence the expression of FoxM1; this requires further investigation.

In conclusion, our results suggest that FoxM1 and Her-2 are important diagnostic markers for gastric cancer. FoxM1 could be a potential cellular target for therapeutic intervention, particularly in Her2-targeted therapy-resistant cancers.

Acknowledgements

This study was supported by a grant from the Medicine and Healthy Technology Development Program of Shandong province (2011HZ028).

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June-2014
Volume 33 Issue 6

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Copy and paste a formatted citation
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Spandidos Publications style
Qi W, Li X, Zhang Y, Yao R, Qiu W, Tang D and Liang J: Overexpression of Her-2 upregulates FoxM1 in gastric cancer. Int J Mol Med 33: 1531-1538, 2014
APA
Qi, W., Li, X., Zhang, Y., Yao, R., Qiu, W., Tang, D., & Liang, J. (2014). Overexpression of Her-2 upregulates FoxM1 in gastric cancer. International Journal of Molecular Medicine, 33, 1531-1538. https://doi.org/10.3892/ijmm.2014.1732
MLA
Qi, W., Li, X., Zhang, Y., Yao, R., Qiu, W., Tang, D., Liang, J."Overexpression of Her-2 upregulates FoxM1 in gastric cancer". International Journal of Molecular Medicine 33.6 (2014): 1531-1538.
Chicago
Qi, W., Li, X., Zhang, Y., Yao, R., Qiu, W., Tang, D., Liang, J."Overexpression of Her-2 upregulates FoxM1 in gastric cancer". International Journal of Molecular Medicine 33, no. 6 (2014): 1531-1538. https://doi.org/10.3892/ijmm.2014.1732