Low FTO expression serves as a potential biomarker for diagnosis and prognosis of patients with liver cancer

doi:10.21203/rs.3.rs-1408109/v1

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Low FTO expression serves as a potential biomarker for diagnosis and prognosis of patients with liver cancer

https://doi.org/10.21203/rs.3.rs-1408109/v1

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Background: As an important part of m⁶A modification, FTO plays a carcinogenic effect in cancer. In this study, we aim to explore whether FTO could be a new target for diagnosis and prognostic of patients with liver cancer.

Material and Methods: We obtained and analysis data from TCGA database by using R software (version 3.5.1). The box plot was used to analyze the pattern of FTO expression. Receiver operating characteristic (ROC) curve was performed to evaluate diagnostic value of FTO expression in liver cancer. Fisher’s exact and chi-square tests were used to analyze relationship between FTO expression and clinical pathological characteristics. Kaplan-Meier curve and Cox regression analysis were used to explore the prognostic value of FTO in liver cancer.

Results: We observed that FTO was down-regulated in liver cancer and was associated with patients’ age. ROC curve showed that FTO expression had good clinical diagnostic value. Our results also revealed that FTO expression was associated with age, histologic grade, M classification, vital status, and overall survival (OS) of patients. Low FTO expression decreased OS, and was an independent predictor of poor prognosis in patients with liver cancer.

Conclusion: FTO could serves as a potential biomarker for the diagnosis and prognosis of liver cancer

Liver cancer

N6-methyladenosine

FTO

biomarker

prognosis

diagnosis

Liver cancer is a malignant tumor associated with high recurrence and metastasis rate^1–3. Despite tremendous progress had been made in the development of early diagnosis and comprehensive therapy, its incidence and mortality have been steadily increasing^4,5. The main reason is local recurrence and distant organ metastasis after surgical treatment, leading to poor prognosis and shortened survival time of patients⁶. With the research on cancer treatment strategies and prognosis prediction, molecular targets had become a novel clinical strategy⁷. Therefore, it is very meaningful and important to explore new molecular markers related to liver cancer.

N⁶-methyladenosine (m⁶A) is a dominant RNA methylation modification. This methylation modification has been proven to be reversible, and it was involved in three types of main proteins, including transmethylase (m⁶A“writer”),demethylase(m⁶A “eraser”) and methylation reading protein (m⁶A “reader”)^8,9. The m⁶A “writer” was responsible for the methylation of target RNA transcripts¹⁰. The main function of m⁶A “reader” was to identify m⁶A modifications to guide RNA translation, splicing, export, degradation and microRNA processing

⁸.The m⁶A "eraser" was responsible for removing m⁶A from the target transcript^8,10,11.Studies have shown that the dysregulation of m⁶A-related molecules affects the tumorigenesis, indicating that m⁶A was closely relevant to tumor occurrence and tumor progression¹².

FTO (fat mass and obesity associated protein), the first identified m⁶A demethylase, was able to control mRNA splicing by inhibiting SRSF2 binding at the splice site^13–15. In addition, FTO also blocked YTHDF2-mediated mRNA degradation by reducing m⁶A levels of cyclin A2 and cyclin-dependent kinase 2 (CDK2), leading to promote adipocyte cycle progression and fat formation^16,17. Recently, studies have shown that FTO played a carcinogenic effect in cancer^18–20. It was reported that FTO induced drug resistance in tumor cells after drug treatment²¹. For example, knocking out FTO can significantly enhance response of acute myelocytic leukemia (AML) cells to all-transretinoic acid (ATRA) treatment, thereby promoting differentiation²². Similarly, in cutaneous squamous cell carcinoma (CSCC), FTO increased the resistance of tumor cells to radiotherapy and chemotherapy by removing m⁶A from beta-catenin²³. At present, the expression level of FTO has been studied as a potential biomarker for various cancers, such as gastric cancer²⁴, intrahepatic cholangiocarcinoma²⁵and endometrial cancer²⁶. However, the potential role of FTO expression in the clinical diagnosis and prognostic evaluation of liver cancer patients has not been determined.

In the current study, we compared the expression of FTO mRNA between liver cancer patients and healthy individuals, and analyzed the diagnostic and prognostic significance of FTO expression. We also studied the correlation between FTO expression and clinic-pathological parameters. The results revealed that FTO expression is an independent risk factor for poor survival, indicating that FTO may be a useful biomarker for the prognosis of liver cancer.

Database selection and data collection

We obtained RNA-Seq of FTO and clinical information of liver cancer patients from The Cancer Genome Atlas (TCGA) dataset. RNA-Seq was transformed to RSEM by estimating as log2(x + 1) normalized counts and used for subsequent analysis by selecting R software (version 3.5.1)²⁷.

Statistical analysis

The package ggplot2 in R software is used for visual analysis. The box plot showed the expression of FTO in the LIHC dataset. Chi-square test was used to evaluate the correlation between FTO expression and clinical features of liver cancer patients. The ROC curve was used to evaluate the diagnostic significance of FTO expression in liver cancer. The Kaplan-Meier curve was performed to assess the effect of FTO expression on patient’s survival (OS and RFS). The univariate and multivariate Cox analysis was used to analyze the prognostic value of FTO expression. P < 0.05 is considered statistically significant.

The expression pattern of FTO in liver cancer patients

Through using R software, clinical data of 373 patients were collected from the TCGA database, including the patient’s age, gender, histological type, histologic grade, clinical stage, and TNM classification, as well as radiation therapy, residual tumor, vital status, sample type overall survival and relapse-free survival (Table 1). Subsequently, in order to analyze the expression pattern of FTO, we analyzed the expression of FTO in 52 healthy individuals and 373 patients. As shown in Fig. 1, FTO expression was significantly lower in tumor tissues than that in normal tissues (P = 0.026). In addition, differences in FTO expression was found according to age (P = 0.039).

Table 1

Demographic and clinical characteristics of TCGA-LIHC cohort
characteristics	Numbers of cases(%)
Age
< 55	117(31.45)
>=55 NA	255(68.55) 1(0)
Gender
Female	121(32.44)
Male	252(67.56)
Histological type
Fibrolamellar Carcinoma	3(0.8)
Hepatocellular Carcinoma	363(97.32)
Hepatocholangiocarcinoma (Mixed)	7(1.88)
Histologic grade
NA	5(1.34)
G1	55(14.75)
G2	178(47.72)
G3	123(32.98)
G4	12(3.22)
Stage
NA	24(6.43)
I	172(46.11)
II	87(23.32)
III	85(22.79)
IV	5(1.34)
T classification
NA	2(0.54)
T1	182(48.79)
T2	95(25.47)
T3	80(21.45)
T4	13(3.49)
TX	1(0.27)
N classification
NA	1(0.27)
N0	253(67.83)
N1	4(1.07)
NX	115(30.83)
M classification
M0	267(71.58)
M1	4(1.07)
MX	102(27.35)
Radiation therapy
NA	25(6.7)
No	340(91.15)
Yes	8(2.14)
Residual tumor
NA	7(1.88)
R0	326(87.4)
R1	17(4.56)
R2	1(0.27)
RX	22(5.9)
Vital status
Deceased	130(34.85)
Living	243(65.15)
Sample type
Primary Tumor	371(99.46)
Recurrent Tumor	2(0.54)
Overall survival
No	237(64.58)
Yes	130(35.42)
Relapse-free survival
No	179(55.94)
Yes	141(44.06)
HK3
high	282(75.6)
low	91(24.4)
Abbreviation: NA, not available.

Diagnostic significance of FTO expression in liver cancer

To evaluate the diagnostic significance of FTO expression, we established ROC curve using the expression value of liver cancer patients and healthy individuals from TCGA. We found that FTO expression had diagnostic value overall (AUC = 0.597; Fig. 2). Subsequently, we analyzed the diagnostic value of FTO expression in different stages of liver cancer, including stage I (AUC = 0.610), stage II (AUC = 0.628), stage III (AUC = 0.550) and stage IV (AUC = 0.672).

Correlation between FTO expression and clinical characteristics of liver cancer.

To further analyze the correlation between FTO expression and clinical characteristics, we divided patients into two groups (high expression and low expression of FTO expression) according to the ROC curve threshold (Fig. 2A). As shown in Table 2, the chi-square test indicated low FTO expression was significantly associated with age (P = 0.0079), histologic grade (P = 0.0088), M classification(P = 0.0023), vital status (P = 0.0227) and overall survival of patients (P = 0.0216).

Table 2

Correlation between the expressions of *FTO*and the clinic pathologic characteristics in liver cancer
Parameter	variables	N	FTO				X2	P-value	Fish
Parameter	variables	N	high	prop	low	prop	X2	P-value	Fish
Age	< 55	117	78	(27.66)	39	(43.33)	7.0642	0.0079	0.0063
	>=55	255	204	(72.34)	51	(56.67)
Gender	Female	121	91	(32.27)	30	(32.97)	0	1	0.8982
	Male	252	191	(67.73)	61	(67.03)
Histological_type	Fibrolamellar Carcinoma	3	3	(1.06)	0	(0)	1.387	0.4998	1
	Hepatocellular Carcinoma	363	273	(96.81)	90	(98.9)
	Hepatocholangiocarcinoma (Mixed)	7	6	(2.13)	1	(1.1)
Histologic_grade	G1	55	47	(16.91)	8	(8.89)	11.4123	0.0097	0.0088
	G2	178	142	(51.08)	36	(40)
	G3	123	81	(29.14)	42	(46.67)
	G4	12	8	(2.88)	4	(4.44)
Stage	I	172	136	(51.91)	36	(41.38)	5.5806	0.1339	0.1195
	II	87	63	(24.05)	24	(27.59)
	III	85	61	(23.28)	24	(27.59)
	IV	5	2	(0.76)	3	(3.45)
T_classification	T1	182	145	(51.79)	37	(40.66)	4.4394	0.3498	0.324
	T2	95	69	(24.64)	26	(28.57)
	T3	80	55	(19.64)	25	(27.47)
	T4	13	10	(3.57)	3	(3.3)
	TX	1	1	(0.36)	0	(0)
N_classification	N0	253	185	(65.84)	68	(74.73)	2.5685	0.2769	0.207
	N1	4	3	(1.07)	1	(1.1)
	NX	115	93	(33.1)	22	(24.18)
M_classification	M0	267	194	(68.79)	73	(80.22)	12.0013	0.0025	0.0023
	M1	4	1	(0.35)	3	(3.3)
	MX	102	87	(30.85)	15	(16.48)
Radiation_therapy	No	340	256	(97.34)	84	(98.82)	0.1429	0.7054	0.6851
	Yes	8	7	(2.66)	1	(1.18)
Residual_tumor	R0	326	242	(88)	84	(92.31)	5.1227	0.163	0.2034
	R1	17	14	(5.09)	3	(3.3)
	R2	1	0	(0)	1	(1.1)
	RX	22	19	(6.91)	3	(3.3)
Vital_status	Deceased	130	89	(31.56)	41	(45.05)	4.9396	0.0262	0.0227
	Living	243	193	(68.44)	50	(54.95)
Sample_type	Primary Tumor	371	280	(99.29)	91	(100)	0	1	1
	Recurrent Tumor	2	2	(0.71)	0	(0)
Overall survival	No	237	189	(67.99)	48	(53.93)	5.2222	0.0223	0.0216
	Yes	130	89	(32.01)	41	(46.07)
Relapse-free survival	No	179	140	(56.22)	39	(54.93)	0.0034	0.9534	0.8925
	Yes	141	109	(43.78)	32	(45.07)

Effect of FTO expression on patient survival in liver cancer

We performed survival analysis to evaluate the effect of FTO expression on the survival of liver cancer patients. As shown in Fig. 3, Kaplan-Meier curves showed that the patients of low FTO expression significantly had the poor overall survival (P = 0.011). Subgroups analysis found that low FTO expression significantly affects patient OS in stage G1/G2, stage Ⅰ/Ⅱ (P = 0.0098), T1 (P = 0.033), N0 (P = 0.016) and M0 (P = 0.018). We also observed that female patients with low FTO expression had shorter OS (P = 0.014), and elder patient (P = 0.0025). However, the low expression of FTO had no significant effect on patients' RFS (Fig. 4).

Low FTO expression is an independent risk factor for patient’s prognosis.

To assess the prognostic significance of FTO expression in liver cancer, univariate Cox analysis and multivariate Cox analysis were performed. We selected potential variables that make sense in univariate analysis to conduct multivariable Cox analysis (Tables 3 and 4). We found that low FTO expression is an independent risk factor for poor OS (hazard ratio [HR] = 0.62, 95% confidence interval [CI]:0.43–0.91, P = 0.014). In addition, in our results, FTO expression cannot be used as an independent predictor of RFS.

Table 3

Summary of univariate and multivariate Cox regression analyses of overall survival duration
Parameters	Univariate analysis			Multivariate analysis
Parameters	Hazard Ratio	95%CI (lower ~ upper)	P value	Hazard Ratio	95%CI (lower-upper)	P value
Age	1	0.69–1.45	0.997
Gender	0.8	0.56–1.14	0.22
Histologicgrade	1.04	0.84–1.3	0.698
stage	1.38	1.15–1.66	0.001	0.84	0.67–1.05	0.123
Tclassification	1.66	1.39–1.99	0	1.85	1.47–2.34	0
Nclassification	0.73	0.51–1.05	0.086
Mclassification	0.72	0.49–1.04	0.077
Radiationtherapy	0.51	0.26–1.03	0.06
Residualtumor	1.42	1.13–1.8	0.003	1.45	1.13–1.86	0.004
FTO	0.62	0.43–0.9	0.011	0.62	0.43–0.91	0.014

Table 4

Summary of univariate and multivariate Cox regression analyses of relapse-free survival duration
Parameters	Univariate analysis			Multivariate analysis
Parameters	Hazard Ratio	95%CI (lower ~ upper)	P value	Hazard Ratio	95%CI (lower-upper)	P value
Age	0.9	0.63–1.28	0.55
Gender	0.99	0.7–1.41	0.966
Histologicgrade	0.98	0.8–1.21	0.883
stage	1.66	1.38–1.99	0	1.13	0.88–1.46	0.333
Tclassification	1.78	1.49–2.12	0	1.63	1.26–2.13	0
Nclassification	0.97	0.67–1.4	0.874
Mclassification	1.17	0.79–1.74	0.432
Radiationtherapy	0.74	0.26–2.16	0.584
Residualtumor	1.28	1.01–1.61	0.042	1.33	1.05–1.69	0.017
FTO	0.9	0.61–1.34	0.619

Based on the TCGA-LIHC data set analysis revealed that FTO was down-regulated in liver cancer and was associated with patients’ age. The ROC curve showed that FTO expression was able to be clinical diagnosis marker in the liver cancer. In the analysis of clinical characteristics, FTO expression was related to the patient's age, histological grade, M classification, vital status and OS. Through the survival curve, we found that liver cancer patients with low FTO expression had a worse OS. Univariate and multivariate Cox regression analysis confirmed that FTO is an independent predictor of poor prognosis in patients with liver cancer.

As the first m⁶A “eraser”, indeed, FTO played an oncogenic role in a number of acute myeloid leukemias by enhancing leukemic oncogene-mediated cell transformation: acts by mediating m6A demethylation of target transcripts such as MYC, CEBPA, ASB2 and RARA, leading to promote their expression^18,28. Many studies suggested that FTO was up-regulated in several tumors, including breast cancer²⁹, gastric cancer³⁰and glioblastoma³¹. However, in this study, our results show that FTO played a tumor suppressor effect in liver cancer, which suggested that FTO may play an important role as acontext-related regulator in network signal of tumorigenesis. In addition, we also observed that FTO expression gradually decreased with increasing of histological grade, which meant that it might have a potential negative impact on the progression of liver cancer.

Considering the relationship between immune regulation and anti-tumor effects, it is clear that tumor cells are up-regulated with many new antigens, which may be recognized by the immune system³². In the process of tumorigenesis, tumor cells promote their proliferation and metastasis by escaping from immune host surveillance and attack. It had been reported that FTO promoted the occurrence of gastric cancer by promoting tumor cell proliferation, migration and lymph node metastasis²⁴. Zhang et al. found that FTO induced the growth and invasion of endometrial cancer cells by regulating the PI3K/AKT and MAPK signaling pathways, which indicated that FTO played an important role in evading immune surveillance in tumors³³.These findings indicated that FTO played an important role in tumor proliferation, invasion and metastasis, although no previous studies had directly detected the specific function of FTO in tumor progression. In the present study, we found that the low FTO expression significantly shortened the OS of liver cancer patients, and found that low FTO expression significantly affects patient OS inG1/G2, I/II, T1, N0 and M0. This indicated that FTO expression had predictive prognostic value for specific types of patients, which was beneficial to the selection and supervision of prognostic treatment for patients. Interestingly, FTO expression did not have significant correlation with patients' RFS. We guess this may be related to the limited number of samples or patient's lifestyle. However, the specific reason needs to be further clarified.

Gene expression and genetic characteristics in tumors are related to clinical characteristics, pathological characteristics and patient prognosis³⁴. In liver cancer, several biomarkers related to tumor proliferation signals are associated with poor prognosis of patients, such as TGF-β, KI-67 and PTEN^35–37. Previous studies showed that a reproducible gene-expression signature correlated with survival is present in liver tissue adjacent to the tumor in HCC patients, and can predict the risk of tumor recurrence after postoperative in HCC patients³⁸.Additionally, a large number of studies based on tumor tissue (gene expression profiles and mutation models) are being conducted to discover potential biomarkers for predicting HCC patients³⁹. These studies indicate the importance and feasibility of studying biomarkers of tumor tissue. Therefore, it is necessary to increase efforts to verify the genetic biomarkers related to the prognosis of liver cancer in clinical test.

To our comprehension, this study is the first time to identify the correlation between FTO expression and clinical application value in liver cancer patients. We revealed that FTO may be used as a biomarker for clinical diagnosis and poor prognosis of liver cancer. However, due to the limited number of samples, it is difficult to establish a more valuable predictive model between FTO expression and clinicopathological data of liver cancer patients. In future studies, we need to expand the sample size in order to generate an appropriate prediction model for the prognosis of liver cancer patients.

Competing interests:

All authors have completed the ICMJE uniform disclosure form.The authors have no conflicts of interest to declare.

Ethics approval and consent to participate:

Ethics committee approval was not necessary because all clinical data used in this study were obtained from a public database and are available for research.

Consent for publication:

Not applicable

Availability of data and materials:

The results shown here are partly based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga.

Funding:

This project was supported by the foundation of Jilin Provincial Finance Department of China (Grant Number: JLSWSRCZX2021-071 and JLSCZD2019-021) and The First Hospital of Jilin University (Grant Number: JDYY11202008).

Authors' contributions:

Hongyun Shi and Chang Fu wrote the manuscript. Panpan Quan contributed to data collection and analysis. Yan Jiao and Hongyun Shi and Chang Fu had a significant role in the study design and manuscript review. Liyue Zhang revised the manuscript. All authors read and approved the final manuscript.

Acknowledgements:

Not applicable

Marengo, A., Rosso, C. & Bugianesi, E. Liver Cancer: Connections with Obesity, Fatty Liver, and Cirrhosis. Annu Rev Med 67, 103-117, doi:10.1146/annurev-med-090514-013832 (2016).
Aufhauser, D. D.et al. Incidence of Occult Intrahepatic Metastasis in Hepatocellular Carcinoma Treated With Transplantation Corresponds to Early Recurrence Rates After Partial Hepatectomy. Ann. Surg. 267, 922-928, doi:10.1097/sla.0000000000002135 (2018).
Su, Y. H., Kim, A. K. & Jain, S. Liquid biopsies for hepatocellular carcinoma. Transl Res 201, 84-97, doi:10.1016/j.trsl.2018.07.001 (2018).
Cheng, A. L., Shen, Y. C. & Zhu, A. X. Targeting Fibroblast Growth Factor Receptor Signaling in Hepatocellular Carcinoma. Oncology-Basel 81, 372-380, doi:10.1159/000335472 (2011).
Joliat, G. R., Hahnloser, D., Demartines, N. & Schafer, M. Future development of gastrointestinal cancer incidence and mortality rates in Switzerland: a tumour registry- and population-based projection up to 2030. Swiss Med Wkly 145, doi:ARTN w14188 10.4414/smw.2015.14188 (2015).
Zhang, X. F., Li, J., Shen, F. & Lau, W. Y. Significance of presence of microvascular invasion in specimens obtained after surgical treatment of hepatocellular carcinoma. J Gastroen Hepatol 33, 347-354, doi:10.1111/jgh.13843 (2018).
Lachenmayer, A., Alsinet, C., Chang, C. Y. & Llovet, J. M. Molecular approaches to treatment of hepatocellular carcinoma. Digest Liver Dis 42, S264-S272, doi:Doi 10.1016/S1590-8658(10)60515-4 (2010).
He, L. E.et al. Functions of N6-methyladenosine and its role in cancer. Mol Cancer 18, doi:ARTN 176 10.1186/s12943-019-1109-9 (2019).
Chen, B., Li, Y., Song, R. F., Xue, C. & Xu, F. Functions of RNA N6-methyladenosine modification in cancer progression. Molecular Biology Reports 46, 2567-2575, doi:10.1007/s11033-019-04655-4 (2019).
Yue, Y. N., Liu, J. Z. & He, C. RNA N-6-methyladenosine methylation in post-transcriptional gene expression regulation. Genes Dev. 29, 1343-1355, doi:10.1101/gad.262766.115 (2015).
Alarcon, C. R., Lee, H., Goodarzi, H., Halberg, N. & Tavazoie, S. F. N-6-methyladenosine marks primary microRNAs for processing. Nature 519, 482-+, doi:10.1038/nature14281 (2015).
Yang, J., Chen, J., Fei, X., Wang, X. & Wang, K. N6-methyladenine RNA modification and cancer. Oncology letters 20, 1504-1512, doi:10.3892/ol.2020.11739 (2020).
Zhao, X.et al. FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis. Cell Res 24, 1403-1419, doi:10.1038/cr.2014.151 (2014).
Ben-Haim, M. S., Moshitch-Moshkovitz, S. & Rechavi, G. FTO: linking m(6)A demethylation to adipogenesis. Cell Res 25, 3-4, doi:10.1038/cr.2014.162 (2015).
Mathiyalagan, P.et al. FTO-Dependent N-6-Methyladenosine Regulates Cardiac Function During Remodeling and Repair. Circulation 139, 518-532, doi:10.1161/Circulationaha.118.033794 (2019).
Wu, R. F.et al. FTO regulates adipogenesis by controlling cell cycle progression via m(6)A-YTHDF2 dependent mechanism. Bba-Mol Cell Biol L 1863, 1323-1330, doi:10.1016/j.bbalip.2018.08.008 (2018).
Wu, R. F.et al. Epigallocatechin gallate targets FTO and inhibits adipogenesis in an mRNA m(6)A-YTHDF2-dependent manner. Int J Obesity 42, 1378-1388, doi:10.1038/s41366-018-0082-5 (2018).
Li, Z. J.et al. FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N-6-Methyladenosine RNA Demethylase. Cancer Cell 31, 127-141, doi:10.1016/j.ccell.2016.11.017 (2017).
Chen, J. L. & Du, B. Novel positioning from obesity to cancer: FTO, an m(6)A RNA demethylase, regulates tumour progression. J Cancer Res Clin 145, 19-29, doi:10.1007/s00432-018-2796-0 (2019).
Huang, Y.et al. Small-Molecule Targeting of Oncogenic FTO Demethylase in Acute Myeloid Leukemia. Cancer Cell 35, 677-+, doi:10.1016/j.ccell.2019.03.006 (2019).
Yan, F.et al. A dynamic N-6-methyladenosine methylome regulates intrinsic and acquired resistance to tyrosine kinase inhibitors. Cell Res 28, 1062-1076, doi:10.1038/s41422-018-0097-4 (2018).
Cui, Q.et al. m(6)A RNA Methylation Regulates the Self-Renewal and Tumorigenesis of Glioblastoma Stem Cells. Cell Reports 18, 2622-2634, doi:10.1016/j.celrep.2017.02.059 (2017).
Zhou, S.et al. FTO regulates the chemo-radiotherapy resistance of cervical squamous cell carcinoma (CSCC) by targeting -catenin through mRNA demethylation. Mol Carcinogen 57, 590-597, doi:10.1002/mc.22782 (2018).
Xu, D.et al. FTO expression is associated with the occurrence of gastric cancer and prognosis. Oncology Reports 38, 2285-2292, doi:10.3892/or.2017.5904 (2017).
Rong, Z. X.et al. Downregulation of Fat Mass and Obesity Associated (FTO) Promotes the Progression of Intrahepatic Cholangiocarcinoma. Front. Oncol. 9, doi:ARTN 369 10.3389/fonc.2019.00369 (2019).
Delahanty, R. J.et al. Association of Obesity-related Genetic Variants With Endometrial Cancer Risk: A Report From the Shanghai Endometrial Cancer Genetics Study. Am J Epidemiol 174, 1115-1126, doi:10.1093/aje/kwr233 (2011).
Shim, S. R. & Kim, S. J. Intervention meta-analysis: application and practice using R software. Epidemiology and health 41, e2019008, doi:10.4178/epih.e2019008 (2019).
Su, R.et al. R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m(6)A/MYC/CEBPA Signaling. Cell 172, 90-+, doi:10.1016/j.cell.2017.11.031 (2018).
Tan, A. H., Dang, Y. W., Chen, G. & Mo, Z. N. Overexpression of the fat mass and obesity associated gene (FTO) in breast cancer and its clinical implications. Int J Clin Exp Patho 8, 13405-13410 (2015).
Li, Y.et al. Expression of Demethylase Genes, FTO and ALKBH1, Is Associated with Prognosis of Gastric Cancer. Dig. Dis. Sci. 64, 1503-1513, doi:10.1007/s10620-018-5452-2 (2019).
Deng, X. L., Su, R., Stanford, S. & Chen, J. J. Critical Enzymatic Functions of FTO in Obesity and Cancer. Front Endocrinol 9, doi:UNSP 396 10.3389/fendo.2018.00396 (2018).
Tang, H. D., Qiao, J. & Fu, Y. X. Immunotherapy and tumor microenvironment. Cancer Lett 370, 85-90, doi:10.1016/j.canlet.2015.10.009 (2016).
Zhang, Z. B.et al. Estrogen induces endometrial cancer cell proliferation and invasion by regulating the fat mass and obesity-associated gene via PI3K/AKT and MAPK signaling pathways. Cancer Lett 319, 89-97, doi:10.1016/j.canlet.2011.12.033 (2012).
Jiao, Y., Li, Y. Q., Lu, Z. Y. & Liu, Y. H. High Trophinin-Associated Protein Expression Is an Independent Predictor of Poor Survival in Liver Cancer. Dig. Dis. Sci. 64, 137-143, doi:10.1007/s10620-018-5315-x (2019).
Zucman-Rossi, J., Villanueva, A., Nault, J. C. & Llovet, J. M. Genetic Landscape and Biomarkers of Hepatocellular Carcinoma. Gastroenterology 149, 1226-+, doi:10.1053/j.gastro.2015.05.061 (2015).
Denkert, C.et al. Strategies for developing Ki67 as a useful biomarker in breast cancer. Breast 24, S67-S72, doi:10.1016/j.breast.2015.07.017 (2015).
Li, S. T.et al. Loss of PTEN expression in breast cancer: association with clinicopathological characteristics and prognosis. Oncotarget 8, 32043-32054, doi:10.18632/oncotarget.16761 (2017).
Hoshida, Y.et al. Gene Expression in Fixed Tissues and Outcome in Hepatocellular Carcinoma. New Engl J Med 359, 1995-2004, doi:10.1056/NEJMoa0804525 (2008).
King, L. Y.et al. A genomic and clinical prognostic index for hepatitis C-related early-stage cirrhosis that predicts clinical deterioration. Gut 64, 1296-1302, doi:10.1136/gutjnl-2014-307862 (2015).

No competing interests reported.

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Low FTO expression serves as a potential biomarker for diagnosis and prognosis of patients with liver cancer

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Abstract

Figures

Introduction

Materials And Methods

Database selection and data collection

Statistical analysis

Results

The expression pattern of FTO in liver cancer patients

Diagnostic significance of FTO expression in liver cancer

Correlation between FTO expression and clinical characteristics of liver cancer.

Effect of FTO expression on patient survival in liver cancer

Low FTO expression is an independent risk factor for patient’s prognosis.

Discussion

Declarations

Competing interests:

Ethics approval and consent to participate:

Consent for publication:

Availability of data and materials:

Funding:

Authors' contributions:

Acknowledgements:

References

Competing Interests

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