IFITM2  is a prognostic in  colorectal cancer  and  promotes  progression by activating PI3K/AKT pathway

doi:10.21203/rs.3.rs-1974035/v1

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IFITM2 is a prognostic in colorectal cancer and promotes progression by activating PI3K/AKT pathway

https://doi.org/10.21203/rs.3.rs-1974035/v1

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Objective To investigate the expression of IFITM2 in colorectal cancer(CRC) and explore the effect of IFITM2 on proliferation, migration and invasion ability.

Methods TCGA database was used to analysis the expression of IFITM2 in colorectal cancer, Western blot was chosen to detect the protein level of IFITM2 in colorectal cancer specimens and cell lines. Univariate and multivariate cox regression were used to analyze the association between IFITM2 and clinicopathological features. Kaplan-Meier Plotter tool was selected to evaluate the prognostic significance of IFITM2 gene expression in the TCGA database. A network comprising 50 most similar genes and IFITM2 was constructed with the STRING database. Gene set enrichment analysis (GSEA) was performed using LinkedOmics database. Transient transfection of IFITM2 siRNA and negative control was selected to construct SW480, HCT116 IFITM2 silence cells and control cells. CCK-8 and colony formation assays were selected to observe the effect of IFITM2 on CRC proliferation ability, transwell assays and wound healing assays were used to detect the effect of IFITM2 on CRC cell migration and invasion ability. Gene Set Enrichment Analysis (GSEA) was used to analyze IFITM2-associated pathways and Western blot was used for further verification.

Results IFITM2 was over-expressed in CRC tissues and cells, High IFITM2 expression in CRC was obviously related to N stage, M stage and Pathologic stage. IFITM2 was a significant risk factor influencing the survival of CRC patients. The proliferation ability of SW480 and HCT116 cells was suppressed when IFITM2 was silenced, transwell assays showed IFITM2 silence weaken the migration and invasion ability of CRC cells. GSEA analysis showed IFITM2 was positively related with PI3K/AKT pathway, Western blot results confirmed that IFITM2 could activate PI3K/AKT pathway.

Conclusion IFITM2 was over-expressed in colorectal cancer and modulated PI3K/AKT pathway to promote CRC cells proliferation and metastasis.

IFITM2

Colorectal cancer

PI3K/AKT pathway

proliferation

metastasis

Colorectal cancer (CRC) is a common gastrointestinal tract malignant tumor that seriously threatens the health of the world. The mortality and morbidity of CRC are relatively high in China^[1]. Excessive proliferation and metastasis of tumor cells are the main cause of death in colorectal cancer patients^[2]. Numerous studies have confirmed that the aberrant activation of signaling pathways is an important trigger for tumour development^[3]. Among them, PI3K/AKT signaling pathway is one of the most classical tumor signaling pathways, which widely regulates various biological behaviors, such as tumor metabolism, proliferation, motility and survival^{[4, 5]}. Therefore, elucidating the molecular mechanisms regulating the PI3K/AKT signaling pathway and searching for its potential regulatory genes are expected to provide a new direction for the treatment of CRC.

Interferon-induced transmembrane proteins (IFITMs) is a class of interferon-induced transmembrane proteins with molecular weights of between 10-15Kd, including four functional members: IFITM1, IFITM2, IFITM3 and IFITM5^{[6, 7]}. Initially, IFITMs studies were found to play an important role in the antiviral response in eukaryotes, and recent studies confirmed it plays an important role in the development of tumors. Some studies have reported that IFITM2 is abnormally expressed in esophageal cancer, lung cancer, gastric cancer, glioma and other tumors, and is involved in biological behaviors such as tumor proliferation, migration and invasion^[8–12]. However, the expression and biological function of IFITM2 in CRC remain unclear.

The TCGA datasets

The CRC patient datasets (n=698), including clinical materials and transcriptome sequencing data, were retrieved from TCGA(www.tcga-data.nci.nih.gov/tcga/) utilizing the R package (V3.6.2). Patients with insufficient information on OS, TNM stage and gene expression data were excluded. Lastly, 644 patients were screened in this study, including 50 pairs of cancer tissue and adjacent tissue.

Bioinformatic analysis

Differential expression levels of IFITM2 in 36 cancer types were determined with TIMER (https://cistrome.shinyapps.io/timer/)^[13]. The mRNA levels of IFITM2 in TCGA-COADREAD datasets were analyzed via the UALCAN database (http://ualcan.path.uab.edu/)^[14]. The protein levels of IFITM2 were analyzed by the Human Protein Atlas (https://www.proteinatlas.org/)^[15]. The effect of IFITM2 on survival rates was assessed by Kaplan-Meier Plotter (https://kmplot.com/analysis/)^[16]. A network composed of IFITM2 and their 10 similar neighboring genes was constructed using STRING database (https://cn.string-db.org/cgi/)^[17]. Gene function annotation and pathway analysis was analyzed via the LinkedOmics database (http://www.linkedomics.org/login.php)^[18]. GSEA analysis^[19] was conducted to determine the biological and functional pathways between high and low expression of IFITM2.

Cell culture and treatment

HT29, SW480, HCT116, LOVO, RKO and NCM460 cell lines were supplied by SIBS, CAS (Shanghai, China). TGF-β1 and its inhibitor SB431542 (SB) were obtained from Selleck (Shanghai, China). All cells were grown in 6-well plates with 10% FBS (HyClone, USA)-containing RPMI 1640 medium, and maintained at 37°C and 5% CO₂.

RT-qPCR assays

Total RNA was extracted with TRIzol reagent (TakaraBio, Japan). cDNA synthesis was initiated with First Strand cDNA Synthesis kit (TakaraBio) by following the kit’s protocols. RT-qPCR was conducted using a LightCycler 480 v1.5 system (Roche, Penzberg, Germany). The primers used were: IFITM2, 5’-TGTATCCCACGTACTCTATCTTCC-3’ and 5’-GGACAGGGCGAGGAATGG-3’; GAPDH, 5’-ACCCAGAAGACTGTGGATGG-3’ and 5’-TCTAGACGGCAGGTCAGGTC-3’.

Western blotting

Western blotting was performed in accordance with the previous standard protocol. The primary antibodies used were: IFITM2 (1:500, A15133, Abclonal, Woburn, MA, USA), p-PI3K(1:1000, ab32089, Abcam, UK), p-AKT(1:1000, ab8933, Abcam, UK), PI3K(1:1000, ab140307, Abcam, UK), AKT(1:1000, ab38449, Abcam, UK) and GAPDH(1:2000, ab9485, Abcam, UK). The secondary antibody was HRP-labeled anti-rabbit IgG antibody (1:5000, 7074P2, Cell Signaling Technology, USA). Femto ECL Kit (#FD8030, FDbio, Shenzhen, China) was used to visualize the membranes. Finally, protein blots were analyzed with ImageJ (NIH, MD, USA).

siRNA transfection

SW480 and HCT116 cells were transfected with siRNAs (Sangon Biotech, Shanghai, China) using Lipofectamine 2000 (Invitrogen, Carlsbad, CA, US). The siRNA sequences were as follows: siIFITM2, CCAUUCUGCUCAUCAUCAUTT; NC, UUCUCCGAACGUGUCACGUTT. The efficiency of siIFITM2 was evaluated with real-time PCR and Western blotting.

CCK8 Assay

Cells in the logarithmic growth phase from each experimental group were trypsinized, resuspended in complete medium, and cultured overnight in 96-well plates. On the second day, cell proliferation was evaluated by Cell Counting Kit-8 reagent (Abcam) according to the manufacturer’s protocol. Optical density values at 490 nm were detected using a microplate reader (Molecular Devices, Rockford, IL, USA).

Migration assays

Transwell insert chamber (8-μm pore size; Corning, NY, USA) was employed to conduct migration assays according to the kit’s protocol. Briefly, 10% Matrigel (Dow Corning) was employed to pre-coat the upper chamber. The cells (5×10⁴ cells/well) were transferred to the top chamber and incubated for 24 h at 37°C. The images of invaded cells were captured using the inverted microscope.

Wound healing assays

SW480 and HCT116 cell lines were grown in 12-well plates (5×10⁴ cells/well) overnight. Upon reaching ~90% confluence, line-shaped wounds were created by scratching the monolayer with a sterile 10-µl pipette tip. After incubation for 48 h in RPMI 1640 medium containing 1% FBS, the scratched wound areas were observed using an inverted microscope.

Statistical analysis

All data were analyzed with R package v3.6.2 and SPSS version 20.0 (IBM, Chicago, IL, USA). The data were presented as mean ± SEM. Comparison between two groups was performed by Student’s t-test. The statistical significance was set at P<0.05.

Patient’s clinical features

The patient’s information (e.g., age, gender, TNM stage, histological grade, survival status and survival time) were obtained from the TCGA-COADREAD database. After removing cases with missing data, 644 patients were ultimately included (Table 1).

The expression levels of IFITM2

The results of TIMER analysis showed that IFITM2 was over-expressed in CRC (Figure 1A). Based on the data of 50 CRC and adjacent healthy tissue pairs from the TCGA-COADREAD dataset (n=644), IFITM2 was over-expressed in CRC (P<0.001; Figure 1B). The differences in IFITM2 expression between CRC and adjacent healthy tissues were highly significant (P<0.001; Figure 1C), implying that IFITM2 was over-expressed in CRC. Immunohistochemistry-based antibody-specific staining scores in normal and CRC were obtained from the Human Protein Atlas, in which tumor-specific staining was divided into three grades: weak, moderate and strong (Figure 1D). To further validate IFITM2 expression in CRC, Western blotting were performed to assess the levels of IFITM2 in CRC tissues and cells. The levels of IFITM2 protein in CRC specimens and cells were upregulated (Figures 1E, F). These findings are in line with the bioinformatics data. To make our study more precise, we also analyzed the expression of IFITM2 in the UALCAN and GEPIA online tumor database websites. These results suggested that elevated mRNA expression of IFITM2 was predictive of advanced tumor stages. As shown in Figures 2A-F.

Relation between IFITM2 expression and clinical features

The relationships between IFITM2 expression and clinical data in 644 CRC cases were analyzed. Logistic regression analysis was conducted after grouping based on the median expression of IFITM2. The findings demonstrated that high-expression of IFITM2 in CRC was markedly related to N stage (OR = 1.396 for N0 vs. N1 and and N2), M stage (OR = 1.625 for M0 vs. M1) and Pathologic stage (OR = 1.413 for Stage I vs. Stage II, Stage III and Stage IV) (all P<0.05; Table 2). This indicates that CRC patients with IFITM2 upregulation are more susceptible to advanced CRC compared to those with IFITM2 downregulation.

Univariate and multivariate Cox regression analyses for IFITM2 expression

Univariate regression analysis revealed that the factors affecting OS in GC patients were age(P<0.001), T stage(P=0.004), N stage(P<0.001), M stage(P<0.001), histologic grade(P<0.001) and IFITM2(P<0.001) (Table 3). Multivariate regression analysis of these factors showed that N stage (HR=1.486, P=0.025), M stage (HR=3.153, P<0.001), Pathologic stage(HR=2.450, P=0.019) and IFITM2 (HR=2.620, P<0.001) were significant risk factors affecting survival in CRC patients (Table 3 and Figure 3).

Prognostic value of IFITM2 in CRC

Kaplan-Meier plotter were utilized to assess the impact of IFITM2 expression on survival time in CRC. From the TCGA-COADREAD database, IFITM2 downregulation was related to better Overall survival(OS) (HR=1.7, P<0.001) and Recurrence free survival(RFS) (HR=2.57, P=0.037) in CRC (HR=1.49, P=0.018; Figures 4A, B).The diagnostic roles of IFITM2 in CRC were evaluated by receiver operating characteristic (ROC) curve analysis according to TCGA CRC and normal gastric specimens. The area under the ROC curve (AUC) analysis demonstrated that IFITM2 was specific and sensitive for the diagnosis of CRC (AUC=0.844, CI=0.806-0.881, Figure 4C). At the same time, the prediction accuracy of the model was assessed using a calibration chart (Figure 4D). Pathologic stage, M stage, N stage and IFITM2 expression were used to construct a clinical prognostic risk score for CRC (Figure 4E).The results suggested that the IFITM2 expression level could better predict the 1-year, 3-year and 5-year survival of patients. In general, all these results suggested that the IFITM2 expression level correlated with the prognosis of patients with CRC.

Gene function annotation and pathway analysis with high IFITM2 expression

We used LinkedOmics to obtain the significant positive correlation with the IFITM2 gene, and the heatmap shows 50 gene sets that were significantly positively or negatively correlated with IFITM2 (Figures 5A-C). We used GEPIA to detect the five most closely genes for each IFITM2 family member. The STRING database was then applied to construct a network for comprising IFITM2 and the 10 identified genes (Figure 5D). Moreover, GO analysis (Biological function) demonstrated that IFITM2 mainly joins in response to interferon-gamma, response to typer I interferon, collagen metabolic process, response to interferon-beta, etc. In accordance with the STRING results, high expression of IFITM2 proteins may be related to the response to interferon-gamm(Figure 5E).

Knockdown of IFITM2 inhibited the proliferation and migration of colorectal cancer cell lines

IFITM2 was then silenced in SW480 and HCT116 cell lines, and the efficiency of si-IFITM2 examined by RT-qPCR and Western blotting (Figures 6A-C). The most efficient of these (si-1) was used to conduct follow-up experiments. CCK8 results showed that the proliferation of SW480 and HCT116 cells were decreased compared with control cells(P<0.001, Figure 6D); plate cloning showed that SW480 and HCT116 cells were decreased (P <0.001, Figure 4E).The functions of IFITM2 on the invasion and migration of GC were further investigated. Migration and wound healing assays within 48h of incubation demonstrated the attenuated invasion, migration and scratch repair of IFITM2-knockdown CRC cell lines (Figures 6F, G).The results of GSEA pathway enrichment analysis showed that IFITM2 was positively associated with PI3K/AKT pathway (P<0.05, Figure 6H); The expression of p-PI3K and p-AKT decreased after the knockdown of IFITM2 (P<0.01, Figure 6I), suggesting that knockdown of IFITM2 can inhibit the activation of PI3K/AKT pathway.

CRC is a malignant gastrointestinal tumour with high morbidity and mortality worldwide^[20]. Although the survival rate has improved in recent years, the 5-year survival rate of advanced patients is still less than 10%^[21]. Proliferation and metastasis are important features of tumors, and also important factors affecting the prognosis of tumor patients^[22]. Therefore, the search for key molecules that regulate tumor proliferation and metastasis is expected to provide a new treatment strategy for improving the prognosis of colorectal cancer patients.

IFITM2 is a member of the family of interferon-inducible transmembrane proteins, early studies have focused on the mechanisms of the antiviral response^[23]. However, more and more studies have found that IFITM2 is involved in tumor development, and often plays the role of promoting oncogene. Yang et al. found that IFITM2 has a high expression status in renal clear cell carcinoma tissues and cells, and can lead to tumor invasion and metastasis by promoting lymphangiogenesis^[24]. Our previous study has demonstrated that the effect of IFITM2 on epithelial-mesenchymal transition in gastric cancer by activating TGF-β1 pathway^[25]. However, IFITM2 expression and its specific mechanisms in CRC remain unclarified. In our study, we using data obtained from TCGA databases, the expression of IFITM2 has been confirmed in 36 types of cancer. In pan-cancer, the results found that IFITM2 expression varied in different cancer: significantly high expression in colorectal cancer, gastric cancer, renal clear cell carcinoma, bile duct carcinoma, but low expression in bladder urothelial carcinoma, renal chromhobe cell carcinoma, lung squamous cancer, lung adenocarcinoma and endometrial cancer. Thus, it is possible that the functional characteristics of IFITM2 in different tumors may be distinct.

Next, we demonstrated that IFITM2 gene was over-expressed in CRC compared with adjacent healthy tissue, and this over-expression was associated with worse OS and RFS. Western blotting was employed to validate IFITM2 expression in human CRC cells and clinical specimens. These data were consistent with bioinformatics data. From our analysis of the 644 cases of ccRCC, higher IFITM2 expression was positivity related to the N stage, M stage and pathologic stage. Patients with high IFITM2 expression had an increased risk to CRC in the late N stage, M stage and pathologic stage, suggesting that IFITM2 is a tumor-related gene in CRC. ROC analysis revealed that IFITM2 was a prognostic biomarker for CRC, while univariate/multivariate regression analyses further confirmed that IFITM2 expression was a significant prognostic factor of CRC. Taken our results together, IFITM2 can assist diagnosis and predict prognosis of advanced CRC.

IFITM2 is a potential biomarker in some cancers, but its functional mechanism is still elusive^[24–26]. In this study, we demonstrated that interfering with IFITM2 expression inhibited the proliferative potential of colorectal cancer cells. Meanwhile, migration and wound healing assays within 48 h of incubation demonstrated attenuated migration and scratch repair of IFITM2-knockdown CRC cells. These findings indicate that IFITM2 contributes to CRC proliferation, invasion and metastasis.

The occurrence and development of tumors are closely related to the changes of signal pathways. Our previous study has demonstrated that the effect of IFITM2 on epithelial-mesenchymal transition in GC by activating IGF1/IGF1R/STAT3 and TGF-β1/Smad2 pathways^{[25, 26]}. Nonetheless, whether IFITM2 influences CRC development through inflammation has not been investigated. To investigate the molecular mechanism of IFITM2 promoting CRC proliferation and metastasis, Gene set enrichment analysis (GSEA) was conducted to determine the role in IFITM2-associated signaling pathways in CRC. The analysis results suggest that IFITM2 may be associated with the PI3K/AKT signaling pathway. The PI3K/AKT signaling pathway is one of the classical tumor-related pathways, and it plays many important roles in tumor metabolism, proliferation, EMT, and drug resistance^[27–29]. In the classical PI3K/AKT pathway, PI3K kinase is activated by growth factor stimulation, oncogene activation or kinase. The activated PI3K kinase further phosphorylates Akt, and then activates mTORC1 complex to promote protein transcription regulation^[30–32]. In this study, we confirmed that interference with IFITM2 significantly inhibited the PI3K/AKT pathway in CRC cells, suggesting that the cancer promoting effect of IFITM2 in CRC may be related to its regulation of PI3K/AKT signaling pathway.

In conclusion, this study confirmed that IFITM2 was highly expressed in CRC, and the high expression of IFITM2 activated the PI3K/AKT signal pathway in tumor cells and promoted the proliferation and metastasis of CRC. Therefore, IFITM2 is expected to be an effective target to improve the prognosis of CRC patients. This study also provides an experimental basis for targeted intervention of PI3K/AKT pathway related molecules in the treatment of tumor metastasis.

Acknowledgments

Not applicable.

Author contributions

Yonggang Liu and Xi Li designed the research; Yonggang Liu, Junyong Huang and Jiale Wang conducted the experiment; Jiangyuan Huang, and Jiale Wang analyzed the data; all authors wrote the article together and agreed the submission.

Funding

None

Availability of data and materials

The datasets supporting the conclusions of this article are included within the article.

Ethics approval and consent to participate

All methods were carried out in accordance with the Declaration of Helsinki. No ethics approval was required for this work. All utilized public data sets were generated by others who obtained ethical approval.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Author details

1 Department of Oncology, Shunde Hospital, Southern Medical University (The First People^’s Hospital of Shunde), Foshan, 528308, Guangdong, China.

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Table 1 Clinical Characteristics of Patients

n	322	322
Age, n (%)
<=65	139 (21.6%)	137 (21.3%)
>65	183 (28.4%)	185 (28.7%)
Gender, n (%)
Female	156 (24.2%)	145 (22.5%)
Male	166 (25.8%)	177 (27.5%)
T stage, n (%)
T1	5 (0.8%)	15 (2.3%)
T2	62 (9.7%)	49 (7.6%)
T3	215 (33.5%)	221 (34.5%)
T4	39 (6.1%)	35 (5.5%)
N stage, n (%)
N0	179 (28%)	189 (29.5%)
N1	76 (11.9%)	77 (12%)
N2	65 (10.2%)	54 (8.4%)
M stage, n (%)
M0	229 (40.6%)	246 (43.6%)
M1	43 (7.6%)	46 (8.2%)
Pathologic stage, n (%)
Stage I	56 (9%)	55 (8.8%)
Stage II	112 (18%)	126 (20.2%)
Stage III	98 (15.7%)	86 (13.8%)
Stage IV	43 (6.9%)	47 (7.5%)
Age, median (IQR)	68 (57, 75)	68 (58.25, 77)

Table 2 Relation between IFITM2 expression and clinical characteristics

Characteristics	Total(N)	Odds Ratio(OR)	P value
Age (>65 vs. <=65)	644	1.135 (0.831-1.552)	0.426
Gender (Female vs. Male)	644	0.940 (0.689-1.281)	0.693
T stage (T2&T3&T4 vs.T1)	641	1.231 (0.838-1.812)	0.291
N stage (N1&N2 vs. N0)	640	1.396 (1.019-1.913)	0.038
M stage (M1 vs. M0)	564	1.652 (1.107-2.477)	0.014
Pathologic stage (Stage II&Stage III&Stage IV vs. Stage I)	623	1.413 (1.029-1.942)	0.033

Table 3 Univariate and multivariate Cox regression analysis for IFITM2 expression

Characteristics	Univariate analysis		Multivariate analysis
Characteristics	Hazard ratio (95% CI)	P value	Hazard ratio (95% CI)	P value
Age (<=65 vs. >65)	1.939 (1.320-2.849)	<0.001	1.090 (0.293-4.055)	0.897
Gender (Female vs. Male)	1.054 (0.744-1.491)	0.769
T stage (T2&T3&T4 vs.T1)	2.468 (1.327-4.589)	0.004	0.797 (0.080-7.916)	0.847
N stage (N1&N2 vs. N0)	2.627 (1.831-3.769)	<0.001	1.486 (1.038-2.126)	0.025
M stage (M1 vs. M0)	3.989 (2.684-5.929)	<0.001	3.153 (1.903-4.987)	<0.001
Pathologic stage (Stage II&Stage III&Stage IV vs. Stage I)	2.988 (2.042-4.372)	<0.001	2.450 (1.314-4.566)	0.019
IFITM2 (High vs. Low)	4.609 (2.804-7.577)	<0.001	2.620 (1.611-4.261)	<0.001

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IFITM2 is a prognostic in colorectal cancer and promotes progression by activating PI3K/AKT pathway

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