Translocation of Methionine Adenosyl Transferase MAT2A and Its Prognostic Relevance for Liver Hepatocellular Carcinoma

Pei-Yi Chu; Dev-Aur Chou; Po-Ming Chen; En-Pei Isabel Chiang

doi:10.3390/ijms24109103

Translocation of Methionine Adenosyl Transferase MAT2A and Its Prognostic Relevance for Liver Hepatocellular Carcinoma

Int J Mol Sci. 2023 May 22;24(10):9103. doi: 10.3390/ijms24109103.

Authors

Pei-Yi Chu^{1

2

3

4}, Dev-Aur Chou⁵, Po-Ming Chen⁶, En-Pei Isabel Chiang^{7

8

9}

Affiliations

¹ Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 402, Taiwan.
² School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan.
³ Department of Pathology, Show Chwan Memorial Hospital, Changhua 500, Taiwan.
⁴ National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
⁵ Department of General Surgery, Changhua Show Chwan Memorial Hospital, Changhua 500, Taiwan.
⁶ Research Assistant Center, Show Chwan Memorial Hospital, Changhua 500, Taiwan.
⁷ Department of Food Science and Biotechnology, National Chung Hsing University, Taichung 402, Taiwan.
⁸ Innovation and Development Center of Sustainable Agriculture (IDCSA), National Chung Hsing University, Taichung 402, Taiwan.
⁹ Advanced Plant and Food Crop Biotechnology Center (APFCBC), National Chung Hsing University, Taichung 402, Taiwan.

Abstract

Methionine adenosyl transferases (MATs) catalyze the synthesis of the biological methyl donor adenosylmethionine (SAM). Dysregulation of MATs has been associated with carcinogenesis in humans. We previously found that downregulation of the MAT1A gene enriches the protein-associated translation process and worsens liver hepatocellular carcinoma (LIHC) prognosis. We also discovered that subcellular localization of the MAT2A protein has independently prognostic relevance in breast cancer patients. The present study aimed to examined the clinical relevance of MAT2A translocation in human LIHC. Essential methionine cycle gene expressions in TCGA LIHC datasets were analyzed using Gene Expression Profiling Interactive Analysis 2 (GEPIA2). The protein expression pattern of MAT2A was determined in the tissue array of our own LIHC cohort (n = 261) using immuno-histochemistry, and the prognostic relevance of MAT2A protein's subcellular localization expression was examined using Kaplan-Meier survival curves. LIHC patients with higher MAT2A mRNA expression had a worse survival rate (p = 0.0083). MAT2A protein immunoreactivity was observed in both cytoplasm and nucleus fractions in the tissue array. Tumor tissues had elevated MAT2A protein expression in both cytoplasm and nucleus compared to their adjacent normal tissues. A higher cytoplasmic to nuclear MAT2A protein expression ratio (C/N) was found in female LIHC patients compared to that of male patients (p = 0.047). Kaplan-Meier survival curves showed that a lower MAT2A C/N correlated with poor overall survival in female LIHC patients (10-year survival rate: 29.2% vs. 68.8%, C/N ≤ 1.0 vs. C/N > 1.0, log-rank p = 0.004). Moreover, we found that specificity protein 1 (SP1) may have a potential interaction with nuclear MAT2A protein, using protein-protein interaction; this we found using the GeneMANIA algorithm. We explored the possible protective effects of the estrogen axis in LIHC using the Human Protein Atlas (HPA), and found evidence supporting a possible protective effect of estrogen-related protein ESSRG in LIHC. The localization of SP1 and MAT2 appeared to be inversely associated with ESRRG expression in LIHC. The present study demonstrated the translocation of MAT2A and its prognostic relevance in female LIHC patients. Our findings suggest the potential of estrogen in SP1 regulation and localization of MAT2A, as therapeutic modalities against in female LIHC patients.

Keywords: GNMT; LIHC; MAT1A; MAT2A; prognosis; subcellular localization.

MeSH terms

Carcinoma, Hepatocellular* / metabolism
Female
Humans
Liver Neoplasms* / metabolism
Male
Methionine Adenosyltransferase / metabolism
Prognosis
S-Adenosylmethionine / metabolism
Transferases

Substances

S-Adenosylmethionine
Transferases
Methionine Adenosyltransferase
MAT2A protein, human

Grants and funding

This work was supported by Show Chwan Memorial Hospital grants SRD-111039 (C.P.M.), SRD-111018 (C.P.M.), SRD-110030 (C.P.Y.), SRD-109035 (C.P.Y.), MOST 110-2320-B-005-008-MY3 (C.E.P.), MOST 110-2320-B-005-003-MY3 (C.E.P.). It is also funded in part by the “Innovation and Development Center of Sustainable Agriculture (IDCSA)” and the “Advanced Plant and Food Crop Biotechnology Center (APFCBC) from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan.