Expression of YME1 Like 1 ATPase Increases With the Stage of Adrenocortical Carcinoma Tissue and Is Associated With Poor Patient Prognosis
SHIN-NOSUKE YAMASHITA1,2*, YOSHIATSU TANAKA1,2*, SHAJEDUL ISLAM1,3, TAKAO KITAGAWA1, KAZUHIRO TOKUDA4, DURGA PAUDEL1, SARITA GIRI1, TOHRU OHTA1, FUMIYA HARADA2, HIROKI NAGAYASU2 and YASUHIRO KURAMITSU1,5
“Advanced Research Promotion Centre, 2Division of Oral and Maxillofacial Surgery, School of Dentistry, and
5School of Medical Technology, Health Sciences University of Hokkaido, Tobetsu, Japan;
3Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, U.S.A .; Graduate School of Health and Welfare, Yamaguchi Prefectural University, Yamaguchi, Japan
Abstract
Background/Aim: Adrenocortical carcinoma (ACC) is an endocrine tumor arising in the adrenal cortex. Although its incidence is extremely low, it is highly malignant, rapidly proliferating, and infiltrating surrounding organs, resulting in a poor prognosis. YME1 Like 1 ATPase (YME1L1) is an ATP-dependent metalloprotease that regulates mitochondrial proteostasis. Recently, a correlation between YME1L1 expression and the prognosis of several cancers has been reported. However, no studies have examined the expression level of YME1L1 mRNA in ACC tissues or the relationship between YME1L1 expression and the prognosis of ACC patients. Therefore, there is a need to investigate the relationship between YME1L1 expression and the prognosis of ACC patients.
Materials and Methods: YME1L1 mRNA expression and survival in ACC patients were analyzed using the TCGA database with the UALCAN and GEPIA platforms.
Results: YME1L1 mRNA expression was significantly increased in ACC tissues from stage IV patients compared with stage I, II, and III patients (p<0.0005, p<0.05, and p<0.05, respectively). Furthermore, increased YME1L1 mRNA expression was inversely correlated with survival and disease-free interval in ACC patients (p<0.01).
Conclusion: YME1L1 is highly expressed in ACC tissues and inversely correlated with patient prognosis, suggesting its potential as a prognostic biomarker for ACC patients and providing new insights into its role in tumor biology. Further studies are needed to elucidate its therapeutic significance and mechanistic contribution to the malignant progression of ACC.
Keywords: YME1L1, adrenocortical carcinoma, Kaplan-Meier survival plot, prognosis.
*These Authors contributed equally to this work.
☒ Yasuhiro Kuramitsu, MD, PhD, Advanced Research Promotion Center, Health Sciences University of Hokkaido, 1757 Kanazawa, Tobetsu, Hokkaido 061-0293, Japan. Tel: +81 133231630, e-mail climates@hoku-iryo-u.ac.jp
Introduction
Adrenocortical carcinoma (ACC) is a very rare cancer (0.5- 2.0 cases per million) that originates in the adrenal cortex. Because ACC grows rapidly and invades surrounding organs, the disease is often already advanced by the time it is discovered. As a result, the prognosis for ACC is poor. The 5-year survival rate after tumor resection is 38.6%, with a median survival time of 31.9 months (1). Once metastasis occurs, the 5-year survival rate for patients with ACC is less than 15% (2). If prognostic biomarkers that are highly expressed in the cancer tissues of ACC patients and that are strongly associated with prognosis or that could serve as therapeutic targets were identified, it would be expected that treatment would be more effective. However, at present, there are no clinically useful prognostic biomarkers for ACC.
YME1 Like 1 ATPase (YME1L1) is an ATP-dependent metalloprotease that regulates mitochondrial protein quality control, morphology, and dynamics. It affects mitochondrial homeostasis and resistance to cell stress. Several reports have shown that overexpression of YME1L1 is associated with tumor cell proliferation, survival, and metastasis. High expression of YME1L1 in tumor tissues is observed and correlates with poor prognosis in patients with several solid tumors. Xia et al. reported that YME1L1 expression is elevated in non-small cell lung cancer tissues, and overexpressed YME1L1 in non-small cell lung cancer exerts pro-tumorigenic function (3). Yuan et al. reported YME1L1 as one of the MMP-related prognostic signatures that can predict the prognosis of hepatocellular carcinoma patients (4). Sun et al. showed that YME1L1 mRNA and protein expression was significantly elevated in osteosarcoma tissues from various human patients, and that overexpression of YME1L1 correlated with decreased overall and disease-specific survival in osteosarcoma patients (5). Liao et al. showed that high expression levels of YME1L1 are associated with reduced overall survival and disease-free survival in patients with ovarian cancer (6). However, to date, there have been no reports on YME1L1 in patients with ACC.
The Cancer Genome Atlas (TCGA) is a database and groundbreaking cancer genomics program. TCGA contains data from over 20,000 primary cancers and matched normal samples across 33 cancer types. The program, launched in 2006 by NCI and the National Human Genome Research Institute, is free and available to anyone (7). The University of Alabama at Birmingham’s Cancer Data Analysis Portal (UALCAN) and Gene Expression Profiling Interactive Analysis (GEPIA) are freely available platforms for analyzing TCGA, making it very easy to analyze TCGA cancer patient data, such as mRNA expression and survival curves (8,9).
We have previously analyzed TCGA cancer patient data using the UALCAN and GEPIA platforms and identified and published several candidate prognostic marker genes (10- 16)). In this study, we used these platforms to perform in silico analysis of the TCGA database to investigate the YME1L1 mRNA expression profile in ACC tissues and the possibility that high YME1L1 mRNA expression may affect the survival of ACC patients.
Materials and Methods
Evaluation of YME1L1 expression in tumor tissues from patients with adrenocortical carcinoma (stages I, II, III, and IV). The gene name “YME1L1” is registered in the TCGA database. The expression levels of YME1L1 mRNA in tumor tissues from patients with ACC of various stages registered in the TCGA database were investigated using the UALCAN platform (stage I (n=9), stage II (n=37), stage III (n=16), stage IV (n=15)) (17). mRNA expression data were normalized, and expression values are presented in TPM. Statistical comparisons between stages were performed using Student’s t-test.
Survival analysis according to YME1L1 mRNA expression levels in adrenocortical carcinoma tissues. To investigate the effect of YME1L1 expression levels in ACC on patient survival, survival analyses were performed using the UALCAN platform. The gene name “YME1L1” was entered into the TCGA database, and a median cutoff value was selected to generate Kaplan-Meier curves for ACC patients.
Expression of YME1L1 in ACC based on individual cancer stages
175
p=4.551400E-04
p=2.544300E-02
p=4.774000E-021
Transcript per million
150
125
100
75
50
25
0
Stage1 (n=9)
Stage2 (n=37)
Stage3 (n=16)
Stage4 (n=15)
TCGA samples
Effect of YME1L1 expression level on ACC patient survival
1.00
Survival probability
0.75
0.50
0.25
p=0.0087
Expression level
-High expression (n=20)
0.00
+Low/Medium expression (n=59)
0
1,000
2,000
3,000
4,000
Time (days)
A
Overall Survival
1.0
Low YME1L1 TPM
High YME1L1 TPM
Logrank p=0.0037
0.8
HR(high)=3.2
p(HR)=0.006
Percent survival
n(high)=38
0.6
#
n(low)=38
0.4
0.2
0.0
0
50
100
150
Time (months)
B
Disease Free Survival
1.0
- Low YME1L1 TPM
High YME1L1 TPM
Logrank p=4.5e-06
0.8
HR(high)=5.1
p(HR)=3.1e-05
Percent survival
n(high)=38
0.6
n(low)=38
0.4
0.2
0.0
0
50
100
150
Time (months)
Furthermore, the bioinformatics platform GEPIA was used to investigate the effect of YME1L1 mRNA expression levels on overall survival and disease-free survival in ACC patients, with a p value of less than 0.05 considered statistically significant (9).
Results
YME1L1 mRNA expression was increased in adrenocortical carcinoma tissues from stage IV patients compared to stage I, II, and III patients. We analyzed the TCGA dataset using the UALCAN platform to examine whether increased MCM10 mRNA expression in ACC tissues was dependent on ACC stage. Figure 1A shows MCM10 mRNA expression in ACC by tumor stage (I, II, III, IV; n=9, n=37, n=16, and n=15, respectively). MCM10 mRNA levels were significantly higher in tumor tissues from stage IV patients compared with tumor tissues from stage I, II, and III patients (p=0.00045514, p=0.025443, and p=0.04774, respectively).
Higher YME1L1 mRNA expression levels have been shown to be associated with shorter survival times in patients with adrenocortical carcinoma. Using the UALCAN platform, Kaplan-Meier survival curves were generated for patients with ACC tissues containing high (n=20) and low/intermediate (n=59) YME1L1 expression levels. The results showed that elevated YME1L1 mRNA expression levels correlated with shorter patient survival (p=0.0087) (Figure 2). Furthermore, using the GEPIA platform, Kaplan-Meier survival curves were generated for patients with ACC tissues containing high (n=38) and low (n=38) YME1L1 mRNA expression levels, and overall survival and disease-free survival were analyzed. The results showed that elevated YME1L1 expression levels correlated with shorter overall survival (p=0.0037) (Figure 3A) and disease-free survival (p=0.0000045) (Figure 3B).
Discussion
In this study, we analyzed YME1L1 mRNA expression and Kaplan-Meier survival in patients with ACC using
the bioinformatics platforms GEPIA and UALCAN. The results showed that YME1L1 mRNA expression levels were significantly elevated in ACC tissue from stage IV patients compared to patients with stage I, II, or III ACC. Furthermore, we found that increased YME1L1 mRNA expression correlated with shorter overall survival and disease-free survival in ACC patients.
YME1L1 is a stress-sensitive membrane-anchored mitochondrial protease which regulates proteostasis in the inner mitochondrial membrane and intermembrane space. This protease is rapidly degraded in response to acute oxidative stress. Its carboxy terminus is exposed in the mitochondrial intermembrane space and exists as multiple complexes ranging from 600 to 1,100 kDa. YME1L1 is a key regulator of essential mitochondrial functions, including the maintenance of inner membrane proteostasis and mitochondrial dynamics. YME1L1 supports cell proliferation by acutely restricting mitochondrial biogenesis and degrading mitochondrial protein translocation enzymes, lipid transport proteins, and metabolic enzymes (18-20).
Considering these properties of YME1L1, it is speculated that YME1L1 functions to promote the proliferation and survival of cancer cells. In fact, Sun et al. showed that forced overexpression of YME1L1 enhanced the proliferation and migration of primary osteosarcoma cells, and concluded that overexpressed YME1L1 promotes osteosarcoma cell proliferation by maintaining mitochondrial function and Akt-mTOR activation (5). MacVicar et al. reported that YME1L1- mediated mitochondrial remodeling promotes the growth of pancreatic ductal adenocarcinoma cells as spheroids or xenografts (21). Liao et al. conducted in silico analysis using bioinformatics web resources and tissue microarray analysis using paraffin-embedded tissues from 60 ovarian cancer patients recorded according to the FIGO/TNM classification, and reported that high expression levels of YME1L1 were associated with poor overall survival and disease-free survival (6). Using bioinformatics and tissue analysis, Xia et al. demonstrated that YME1L1 expression is upregulated in human non-small cell lung
cancer (NSCLC) tissues. Furthermore, overexpression of YME1L1 promoted the proliferation and motility of NSCLC cells, suggesting that overexpression of YME1L1 in NSCLC exerts a pro-tumorigenic effect (3). YME1L1 suppresses cell death in response to oxidative stress and regulates mitochondrial morphology through protective control of mitochondrial proteostasis, so increased YME1L1 expression is expected to promote the survival and proliferation of cancer cells. Furthermore, because YME1L1 also enhances the motility and invasiveness of cancer cells, it is understandable that there is an inverse correlation with the prognosis of cancer patients. However, Ando et al. have reported that overexpression of YME1L1 has the opposite effect on neuroblastoma, unlike other cancers. Overexpression of YME1L1 promoted apoptosis in neuroblastoma cells, while knockdown promoted cell proliferation. Furthermore, high YME1L1 expression was significantly associated with improved prognosis in neuroblastoma (22). Therefore, the function of YME1L1 in cancer cells and whether it can be used as a prognostic marker may vary depending on the type of cancer, and further verification is required. To date, there have been no reports on the degree of YME1L1 expression in ACC tissues and the relationship between YME1L1 expression levels and the prognosis of ACC patients.
In this study, by analyzing the TCGA database, we showed that YME1L1 expression is increased in ACC tissue and that patient survival is shortened in inverse proportion to the level of expression, suggesting that YME1L1 may function as a prognostic marker for ACC.
Conflicts of Interest
The Authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Authors’ Contributions
All Authors contributed to the conception and design of the study. Data collection and analysis were performed by
Shin-nosuke Yamashita, Yoshiatsu Tanaka, Shajedul Islam and Yasuhiro Kuramitsu. Shin-nosuke Yamashita and Yoshiatsu Tanaka wrote the first draft of the manuscript, Takao Kitagawa and Yasuhiro Kuramitsu commented on an earlier version of the manuscript. All Authors read and approved the final manuscript.
Artificial Intelligence (AI) Disclosure
No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.
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