Prognostic value of TMEM147 in hepatocellular carcinoma correlates with immune infiltration of hepatocellular carcinoma

doi:10.21203/rs.3.rs-2123138/v1

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Prognostic value of TMEM147 in hepatocellular carcinoma correlates with immune infiltration of hepatocellular carcinoma

https://doi.org/10.21203/rs.3.rs-2123138/v1

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Purpose

At this stage, liver cancer has a poor prognosis and short survival, and there is no clear treatment for this purpose. Therefore, we explored potential future clinical molecular therapeutic targets and biomarkers for survival prognosis prediction that are important for the diagnosis and improved prognosis of patients with hepatocellular carcinoma.

METHODS

We used multiple databases to analyse genes differentially expressed in hepatocellular carcinoma tissue and normal liver tissue, and also analysed the relationship between genes and clinical features, prognosis and immune infiltration.

RESULTS

TMEM147 expression levels were significantly higher in hepatocellular carcinoma tissues than in normal liver tissues, and TMEM147 expression levels were strongly associated with pathological stage, body weight, BMI, pathological grade, adjacent liver tissue inflammation, AFP, and vascular infiltration. Survival analysis showed that high TMEM147 expression had a poor survival rate. Also, NK CD56 + cells, TFH cells, Th2 cells, B cells, CD8+, CD4+, macrophages, and dendritic cells were significantly increased and cytotoxic cells, DC cells, neutrophils, Tcm cells, Th17 cells, and TReg cells were significantly decreased in hepatocellular carcinoma patients in the TMEM147 high expression group.

Conclusion

TMEM147 may be a potential molecular therapeutic target and a biomarker for survival prognosis prediction in the future clinical setting of patients with hepatocellular carcinoma.

database

immune infiltration

survival analysis

tumor microenvironment

According to the International Agency for Research on Cancer (IARC), primary liver cancer will be the sixth most commonly diagnosed cancer and the third leading cause of cancer death worldwide by 2020, with approximately 906,000 new cases, of which approximately 83,000 will be due to liver cancer[1]. Hepatocellular carcinoma accounts for 75–85% of primary liver cancers, making it the most common type of liver cancer[2]. Hepatocellular carcinoma is a malignancy with a high mortality rate, poor prognosis and poor treatment[3]. Epidemiological studies have linked viruses and chemicals to the development of liver cancer[4]. Chronic alcohol abuse, hepatitis B and C, and food contamination with aflatoxin are the main factors contributing to the development of liver cancer[5]. Liver cancer can be treated by liver transplantation or resection[6], transcatheter arterial chemoembolization[7], radiofrequency ablation[8], transarterial radioembolization[9] and targeted chemotherapy[10]. Despite the efforts made so far in the treatment, the recurrence rate at 5 years after surgery is still high[11]. The prognosis for liver cancer is poor, survival is short and there is no clear treatment for this[12]. Therefore, our exploration of potential future clinical molecular therapeutic targets and biomarkers for survival prognosis prediction is of great importance for the diagnosis and improved prognosis of patients with liver cancer.

In this genomic era, there is a vast amount of genetic sequencing technology and data available[13]. These sequencing technologies and genetic data have made a significant contribution to tumour diagnosis and prognosis[14]. The functional state of the endoplasmic reticulum is closely linked to tumour development, so we focused on the transmembrane protein TMEM147, a 25 kDa protein localised to the ER membrane[15, 16] and with seven transmembrane structural domains, its N-terminal located in the ER lumen and its C-terminal facing the cytoplasmic side of the membrane[17], which plays an important role in various physiological processes of the disease. Although the function of TMEM147 remains largely unknown, it is thought to be involved in the regulation of cell proliferation, apoptosis and the transcription of target genes[18]. TMEM147 is known to play an important role in osteosarcoma and colon cancer in the context of existing studies. Based on the current study showing a significant increase in TMEM147 expression in colon cancer, it may be substantially involved in the pathogenesis of colon cancer[19]. In osteosarcoma, TMEM147 expression was negatively correlated with patient prognosis[20]. Several studies have shown that the function of the endoplasmic reticulum is closely related to hepatocellular carcinoma, but TMEM147 has not been reported in hepatocellular carcinoma. The aim of this study was to investigate the relationship between TMEM147 expression levels, and clinical features and immune infiltration in patients with hepatocellular carcinoma, and finally the comparison with the diagnostic value of other hepatocellular carcinoma-related genes.

GEPIA 2.0 Database

The Gene Expression Profiling Interactive Analysis web server(GEPIA2, http://gepia2.cancer-pku.cn) is a specialist website for gene expression analysis of tumour and normal samples based on the TCGA and GTEx databases with 198619 subtypes and 84 cancer subtypes[21]. We used the GEPIA2 database to select liver cancer-related, overall survival, and median gene expression to group most of the differential survival genes, and by comparing with the existing literature, we finally selected the TMEM147 gene. Differential expression of TMEM147 in liver cancer tissues and normal tissues was analysed using GEPIA2.

UALCAN cancer database

UALCAN is a website that enables the exploration, analysis and visualisation of cancer genomic, transcriptomic and proteomic data[22]. We used this site to analyse the difference in expression of the TMEM147 gene in liver cancer tissue and normal tissue and also in relation to survival in patients with liver cancer.

OncoLnc database

OncoLnc is an online analysis site with survival data for 8,647 patients from 21 cancer studies[23]. After we obtained the TMEM147 gene we also validated the relationship between this gene and survival of patients with liver cancer in the Oncolnc database.

Xiantao Academic

Xiantao Academic contains the TCGA database, which uses sequencing data and clinical information for online analysis[24]. We have analysed the relationship between the TMEM147 gene and hepatocellular carcinoma T, N, M and clinical information, immune cells through this website.

Timer database

In the context of tumour immunology research, TIMER (https://cistrome.shinyapps.io/timer/) gives users a website where they can explore and visualise tumour immunology and genomics data[25]. This site includes 10897 samples from TCGA for 32 cancers, as well as a large number of TIIC (tumour infiltrating immune cells) based on a reverse convolution approach to gene expression profiling[26]. In this study, we used the gene module to explore the correlation between TMEM147 expression and levels of immune infiltration (B cells, CD4 + T cells, CD8 + T cells, macrophages, neutrophils and dendritic cells).

Expression of TMEM147 in pan- and hepatocellular carcinoma

Comparing TMEM147 expression between paraneoplastic tissue and tumour samples from the TCGA database, we found that TMEM147 was significantly upregulated in most cancers (Fig. 1A), including liver cancer. This included adrenocortical carcinoma, diffuse large B-cell lymphoma, acute myeloid leukaemia, and low-grade glioma where only tumour tissue was present that was not compared with paraneoplastic tissue. To explore the expression of the TMEM147 gene in liver tissue and tumour tissue, we analysed unpaired samples (Fig. 1B) and paired samples (Fig. 1E) of the gene using the Sento Academic website and found that the TMEM147 gene was significantly more expressed in tumour tissue than in normal tissue (Fig. 1B). Considering that the analysis results of one database may be inaccurate, we therefore used the GEPIA 2.0 and UALCAN databases to analyse the expression of this gene, and the results were (Fig. 1C) and (Fig. 1D) respectively, which also showed that the gene was much more expressed in tumour tissues than in normal tissues.

TMEM147 gene expression correlates with clinical features in patients with hepatocellular carcinoma

We then analysed the relationship between TMEM147 gene and T, N and M stages of hepatocellular carcinoma (Fig. 2a-c). We used GEPIA 2, Sento Academic, UALCAN, and OncoLnc analyses to find that patients with TMEM147 high expression hepatocellular carcinoma had a lower survival rate (Fig. 2d-g). The main clinical characteristics between the TMEM147 low and high expression groups in hepatocellular carcinoma, in relation to a range of clinical information such as pathological stage, gender, age, weight and tumour remnants of hepatocellular carcinoma, where pathological stage, weight, BMI, pathological grade, adjacent liver tissue inflammation, AFP and vascular infiltration were statistically significant, and other clinical information were not statistically significant, are summarised in Table 1.

Table 1
Characteristic	Low expression of TMEM147	High expression of TMEM147	p
n	187	187
T stage, n (%)			0.005**
T1	108 (29.1%)	75 (20.2%)
T2	41 (11.1%)	54 (14.6%)
T3	30 (8.1%)	50 (13.5%)
T4	6 (1.6%)	7 (1.9%)
N stage, n (%)			0.122
N0	126 (48.8%)	128 (49.6%)
N1	0 (0%)	4 (1.6%)
M stage, n (%)			0.624
M0	128 (47.1%)	140 (51.5%)
M1	1 (0.4%)	3 (1.1%)
Pathologic stage, n (%)			0.004**
Stage I	103 (29.4%)	70 (20%)
Stage II	38 (10.9%)	49 (14%)
Stage III	34 (9.7%)	51 (14.6%)
Stage IV	1 (0.3%)	4 (1.1%)
Tumor status, n (%)			0.163
Tumor free	110 (31%)	92 (25.9%)
With tumor	71 (20%)	82 (23.1%)
Gender, n (%)			0.185
Female	54 (14.4%)	67 (17.9%)
Male	133 (35.6%)	120 (32.1%)
Race, n (%)			0.278
Asian	72 (19.9%)	88 (24.3%)
Black or African American	9 (2.5%)	8 (2.2%)
White	99 (27.3%)	86 (23.8%)
Age, n (%)			0.323
<=60	83 (22.3%)	94 (25.2%)
> 60	103 (27.6%)	93 (24.9%)
Weight, n (%)			0.002**
<=70	78 (22.5%)	106 (30.6%)
> 70	96 (27.7%)	66 (19.1%)
Height, n (%)			0.415
< 170	96 (28.2%)	105 (30.8%)
>=170	74 (21.7%)	66 (19.4%)
BMI, n (%)			0.019*
<=25	77 (22.8%)	100 (29.7%)
> 25	91 (27%)	69 (20.5%)
Residual tumor, n (%)			0.392
R0	167 (48.4%)	160 (46.4%)
R1	7 (2%)	10 (2.9%)
R2	0 (0%)	1 (0.3%)
Histologic grade, n (%)			< 0.001***
G1	35 (9.5%)	20 (5.4%)
G2	102 (27.6%)	76 (20.6%)
G3	43 (11.7%)	81 (22%)
G4	5 (1.4%)	7 (1.9%)
Adjacent hepatic tissue inflammation, n (%)			0.027*
None	76 (32.1%)	42 (17.7%)
Mild	47 (19.8%)	54 (22.8%)
Severe	11 (4.6%)	7 (3%)
AFP(ng/ml), n (%)			< 0.001***
<=400	123 (43.9%)	92 (32.9%)
> 400	20 (7.1%)	45 (16.1%)
Albumin(g/dl), n (%)			0.596
< 3.5	39 (13%)	30 (10%)
>=3.5	120 (40%)	111 (37%)
Prothrombin time, n (%)			0.166
<=4	104 (35%)	104 (35%)
> 4	53 (17.8%)	36 (12.1%)
Child-Pugh grade, n (%)			0.429
A	117 (48.5%)	102 (42.3%)
B	9 (3.7%)	12 (5%)
C	1 (0.4%)	0 (0%)
Fibrosis ishak score, n (%)			0.343
0	47 (21.9%)	28 (13%)
1/2	17 (7.9%)	14 (6.5%)
3/4	12 (5.6%)	16 (7.4%)
5/6	45 (20.9%)	36 (16.7%)
Vascular invasion, n (%)			0.007**
No	118 (37.1%)	90 (28.3%)
Yes	44 (13.8%)	66 (20.8%)
Age, median (IQR)	62 (54, 69)	60 (50, 68)	0.123

TMEM147 expression and the level of immune infiltration

Most current treatments for cancer consider only the tumour cells or the choroidal system and rarely consider the host's immune response to treatment[27]. Since both tumour cell activity and immune cells in the tumour microenvironment are involved in the pathogenesis and progression of cancer[28], cancer immunology should receive attention. Tumour-infiltrating immune cells comprise several cell subsets that are key cellular components of the host immune response and important members of the tumour microenvironment[29, 30]. It has been established that tumour-infiltrating immune cells are associated with treatment response and prognosis of liver cancer[27]. Therefore, we analysed the association between TMEM147 and immune cells by using Sento Academic and TIMER. The results of the analysis of the difference in the level of infiltration of TIICs between high and low TMEM147 expression subgroups assessed using the Wilcoxon signed rank test in the Sendo Academic database showed that NK CD56 + cells, TFH cells, and Th2 cells were significantly increased and cytotoxic cells, DC cells, neutrophils, Tcm cells, Th17 cells, and TReg cells were significantly reduced. The association between immune infiltration and TMEM147 expression was assessed by calculating the coefficient of TMEM147 expression and immune infiltration in hepatocellular carcinoma using the TIMER database. The analysis showed that TMEM147 expression levels did not correlate with tumour purity and positively correlated with B cells, CD8+, CD4+, macrophages, neutrophils, and dendritic cells. These findings suggest a specific role for TMEM147 in the immune infiltration of hepatocellular carcinoma.

Comparison of the diagnostic value of TMEM147, DCK and PLEKHA8P1 in hepatocellular carcinoma

Based on the available literature studies, we selected two genes, DCK and PLEKHA8P1, for comparison with TMEM147 in hepatocellular carcinoma. Among them, DCK is an unfavourable prognostic biomarker and is associated with immune infiltration in hepatocellular carcinoma[31]. PLEKHA8P1 promotes tumour progression and indicates poor prognosis in hepatocellular carcinoma[32]. To assess the diagnostic value of TMEM147, we compared the diagnostic value of TMEM147, DCK and PLEKHA8P1. Based on the performance of the ROC curve, the area of the ROC curve for TMEM147 was 0.941, [(CI): 0.918–0.964], with a sensitivity of 86.0%, a specificity of 91.4% and a Jorden index of 0.774. The ROC curve area for DCK was 0.846, with a sensitivity of 86.0% and specificity of 76.2% for DCK. The ROC curve area for PLEKHA8P1 was 0.904, with a sensitivity of 100% and specificity of 66.6% for PLEKHA8P1 and a Jorden index of 0.666. The Jorden index was 0.666, indicating that TMEM147 has a more accurate diagnostic value than DCK and PLEKHA8P1.

Table 2

Diagnostic value of TMEM147, DCK and PLEKHA8P1 for hepatocellular carcinoma
gene	sensitivity (%)	specificity (%)	positive predictive value (%)	negative predictive value (%)
TMEM147	86.0(43/50)	91.4(342/374)	57.3(43/75)	98.0(342/349)
DCK	86.0(43/50)	76.2(285/374)	32.6(43/132)	97.6(285/292)
PLEKHA8P1	100(50/50)	66.6(249/374)	0.286(50/175)	100(249/249)

TMEM147 is a small protein, a member of the transmembrane protein family, localised to the endoplasmic reticulum that plays an important role in various physiological processes in disease, including migration, adhesion and signal transduction regulation[15, 16, 33]. Based on the current study TMEM147 is able to interact with the M3 muscarinic acetylcholine receptor (M3R), suggesting that TMEM147 is transporting and folding M3R through the silencing of TMEM147 in H508 colon cancer cells[16]. It has been shown experimentally that TMEM147 has a broader effect on transmembrane proteins in the endoplasmic reticulum and nuclear envelope, and turns TMEM147 into many additional putative regulator processes and a potential therapeutic target for a range of diseases[34]. Although not all the functions of TMEM147 are understood, in the current literature it has been shown that TMEM147 plays an important role in colon cancer pathogenesis[19] and osteosarcoma prognosis[20].

Here, we have used public database analysis to derive the expression levels of TMEM147 in different cancer types. Among them, the expression levels were higher and statistically significant than normal tissues in a variety of cancers, including liver, bladder uroepithelial, breast, bile duct, colon, oesophagus and glioblastoma multiforme. TMEM147 was associated with the prognosis of hepatocellular carcinoma and renal clear cell carcinoma. In addition, TMEM147 expression level was correlated with pathological stage, body weight, BMI, pathological grade, adjacent liver tissue inflammation, AFP, vascular infiltration and other clinical characteristics, among which we interestingly found a correlation between body weight and TMEM147 expression level. This may be a new way to understand the relationship between TMEM147 and body weight in the future. To date, the biology of TMEM147 in hepatocarcinogenesis and progression is unclear, and few articles have examined the relationship between TMEM147 and hepatocarcinogenesis and progression. Although the function of TMEM147 in hepatocellular carcinoma has not been extensively studied, it is known that high levels of TMEM147 expression are associated with poorer prognosis in hepatocellular carcinoma patients. We also investigated the correlation between TMEM147 expression levels and immune infiltration in hepatocellular carcinoma, and compared the diagnostic value of this gene with that of hepatocellular carcinoma-related genes reported in the existing literature. Our study provides a basis for understanding the potential role of TMEM147 in liver cancer immunity and its use as a biomarker for cancer prognosis in hepatocellular carcinoma.

In the present study, although we have demonstrated that TMEM147 is highly expressed in hepatocellular carcinoma and that higher expression has a lower survival rate, and have investigated the correlation between TMEM147 and clinical features and the level of immune cell infiltration, the main limitations of our study should be noted. Our results are based on bioinformatic analysis. Further experimental validation is needed in the future to further explore the mechanism of TMEM147 gene action in hepatocellular carcinoma.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethics approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Acknowledgments

We have no fund support. Thanks for the help of reviewers, editors and assistants.

Author contributions

jiangZhu conceived and wrote the manuscript, yunfeiKong and junLi provided revision suggestions, xuSong provided part of the corresponding drawings in the manuscript, and jinzhang gave revision suggestions and revised the manuscript.

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No competing interests reported.

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Prognostic value of TMEM147 in hepatocellular carcinoma correlates with immune infiltration of hepatocellular carcinoma

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