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Yen HC, Chen BS, Yang SL, Wu SY, Chang CW, Wei KC, Hsu JC, Hsu YH, Yen TH, Lin CL. Levels of Coenzyme Q 10 and Several COQ Proteins in Human Astrocytoma Tissues Are Inversely Correlated with Malignancy. Biomolecules 2022; 12:336. [PMID: 35204836 PMCID: PMC8869183 DOI: 10.3390/biom12020336] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 02/02/2022] [Accepted: 02/07/2022] [Indexed: 12/12/2022] Open
Abstract
In a previous study, we reported the alterations of primary antioxidant enzymes and decreased citrate synthase (CS) activities in different grades of human astrocytoma tissues. Here, we further investigated coenzyme Q10 (CoQ10) levels and protein levels of polyprenyl diphosphate synthase subunit (PDSS2) and several COQ proteins required for CoQ10 biosynthesis in these tissues. We found that the level of endogenous CoQ10, but not of exogenous α-tocopherol, was higher in nontumor controls than in all grades of astrocytoma tissues. The levels of COQ3, COQ5, COQ6, COQ7, COQ8A, and COQ9, but not of COQ4, were lower in Grade IV astrocytoma tissues than in controls or low-grade (Grades I and II) astrocytomas, but PDSS2 levels were higher in astrocytoma tissues than in controls. Correlation analysis revealed that the levels of CoQ10 and COQ proteins were negatively correlated with malignancy degree and positively correlated with CS activity, whereas PDSS2 level was positively correlated with malignancy. Moreover, lower level of mitochondrial DNA-encoded cytochrome c oxidase subunit 2 was not only associated with a higher malignancy degree but also with lower level of all COQ proteins detected. The results revealed that mitochondrial abnormalities are associated with impaired CoQ10 maintenance in human astrocytoma progression.
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Affiliation(s)
- Hsiu-Chuan Yen
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (B.-S.C.); (S.-L.Y.); (S.-Y.W.); (C.-W.C.)
- Department of Nephrology, Chang Gung Memorial Hospital at Linkou, Taoyuan 333423, Taiwan;
| | - Bing-Shian Chen
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (B.-S.C.); (S.-L.Y.); (S.-Y.W.); (C.-W.C.)
| | - Si-Ling Yang
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (B.-S.C.); (S.-L.Y.); (S.-Y.W.); (C.-W.C.)
| | - Shin-Yu Wu
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (B.-S.C.); (S.-L.Y.); (S.-Y.W.); (C.-W.C.)
| | - Chun-Wei Chang
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; (B.-S.C.); (S.-L.Y.); (S.-Y.W.); (C.-W.C.)
| | - Kuo-Chen Wei
- Department of Neurosurgery, Chang Gung Memorial Hospital at Linkou, Taoyuan 333423, Taiwan;
- Department of Neurosurgery, New Taipei Municipal Tu Cheng Hospital, Chang Gung Medical Foundation, New Taipei City 236017, Taiwan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Jee-Ching Hsu
- Department of Anesthesiology, Lotung Poh-Ai Hospital, Yilan 26546, Taiwan;
| | - Yung-Hsing Hsu
- Department of Neurosurgery, Asia University Hospital, Taichuang 41354, Taiwan;
| | - Tzung-Hai Yen
- Department of Nephrology, Chang Gung Memorial Hospital at Linkou, Taoyuan 333423, Taiwan;
| | - Chih-Lung Lin
- Department of Neurosurgery, Chang Gung Memorial Hospital at Linkou, Taoyuan 333423, Taiwan;
- Department of Neurosurgery, Asia University Hospital, Taichuang 41354, Taiwan;
- Department of Occupational Therapy, Asia University, Taichuang 41354, Taiwan
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Identification of Predictive Biomarkers of Response to HSP90 Inhibitors in Lung Adenocarcinoma. Int J Mol Sci 2021; 22:ijms22052538. [PMID: 33802597 PMCID: PMC7962034 DOI: 10.3390/ijms22052538] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 02/19/2021] [Accepted: 02/27/2021] [Indexed: 12/17/2022] Open
Abstract
Heat shock protein 90 (HSP90) plays an essential role in lung adenocarcinoma, acting as a key chaperone involved in the correct functioning of numerous highly relevant protein drivers of this disease. To this end, HSP90 inhibitors have emerged as promising therapeutic strategies, even though responses to them have been limited to date. Given the need to maximize treatment efficacy, the objective of this study was to use isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomic techniques to identify proteins in human lung adenocarcinoma cell lines whose basal abundances were correlated with response to HSP90 inhibitors (geldanamycin and radicicol derivatives). From the protein profiles identified according to response, the relationship between lactate dehydrogenase B (LDHB) and DNA topoisomerase 1 (TOP1) with respect to sensitivity and resistance, respectively, to geldanamycin derivatives is noteworthy. Likewise, rhotekin (RTKN) and decaprenyl diphosphate synthase subunit 2 (PDSS2) were correlated with sensitivity and resistance to radicicol derivatives. We also identified a relationship between resistance to HSP90 inhibition and the p53 pathway by glucose deprivation. In contrast, arginine biosynthesis was correlated with sensitivity to HSP90 inhibitors. Further study of these outcomes could enable the development of strategies to improve the clinical efficacy of HSP90 inhibition in patients with lung adenocarcinoma.
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Abstract
Humans and other mammals are colonized by microbial agents across the kingdom which can represent a unique microbiome pattern. Dysbiosis of the microbiome has been associated with pathology including cancer. We have identified a microbiome signature unique to ovarian cancers, one of the most lethal malignancies of the female reproductive system, primarily because of its asymptomatic nature during the early stages in development. We screened ovarian cancer samples along with matched, and non-matched control samples using our pan-pathogen array (PathoChip), combined with capture-next generation sequencing. The results show a distinct group of viral, bacterial, fungal and parasitic signatures of high significance in ovarian cases. Further analysis shows specific viral integration sites within the host genome of tumor samples, which may contribute to the carcinogenic process. The ovarian cancer microbiome signature provides insights for the development of targeted therapeutics against ovarian cancers.
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Huang W, Gao F, Li K, Wang W, Lai YR, Tang SH, Yang DH. Decaprenyl diphosphate synthase subunit 2 as a prognosis factor in hepatocellular carcinoma. World J Gastroenterol 2015; 21:3055-3065. [PMID: 25780306 PMCID: PMC4356928 DOI: 10.3748/wjg.v21.i10.3055] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2014] [Revised: 08/21/2014] [Accepted: 10/21/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the involvement of decaprenyl diphosphate synthase subunit 2 (PDSS2) in development and progression of human hepatocellular carcinoma (HCC).
METHODS: PDSS2 protein expression was examined in well- and poorly differentiated HCC tumor samples. The levels of PDSS2 expression were compared with clinical features and prognosis of HCC patients. The effects of PDSS2 on cell proliferation, cell cycle, apoptosis, cell migration, and invasion in HCC HepG2 cells were also investigated.
RESULTS: PDSS2 was downregulated in poorly differentiated cancer samples compared with well-differentiated tumor samples, and the expression level was markedly lower in HCC tissues than in histologically normal tissue adjacent to the cancer. Reduced protein expression was negatively associated with the status of HCC progression. In addition, overexpression of PDSS2 dramatically suppressed cell proliferation and colony formation, and induced apoptosis in HepG2 cells by inducing G1-phase cell-cycle arrest. The migration and invasion capabilities of HepG2 cells were significantly decreased following PDSS2 overexpression.
CONCLUSION: Decreased PDSS2 expression is an unfavorable prognostic factor for HCC, and PDSS2 has potent anticancer activity in HCC tissues and HepG2 cells.
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The tumor-suppressing activity of the prenyl diphosphate synthase subunit 2 gene in lung cancer cells. Anticancer Drugs 2015; 25:790-8. [PMID: 24608273 DOI: 10.1097/cad.0000000000000105] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The prenyl diphosphate synthase subunit 2 (PDSS2) gene has recently been proposed as a novel tumor suppressor in several types of solid tumors. However, the mechanism of its tumor-suppressing activity is not known. Our previous study found a decreased expression of PDSS2 in clinical samples of non-small-cell lung cancer, and an inverse correlation between PDSS2 levels and stages of tumor differentiation and lymph node metastasis. In this study, we further investigated the tumor-suppressing activity of PDSS2 in lung cancer cells using cellular and molecular tools. The PDSS2 gene has low levels of expression in human lung cancer cell lines. We transfected and overexpressed PDSS2 in the NCI-H1299 lung cancer cell line. The forced overexpression caused massive cell death (~70%) through apoptotic pathways and significantly inhibited colony formation. At the same time, repression of PDSS2 expression by siRNA enhanced the growth of a noncancerous lung epithelial cell line MRC-5. There was an inverse correlation (Pearson's test, r=-0.9373) between PDSS2 expression and gelsolin expression, which is known to inhibit apoptosis and enhance cell invasion and metastasis. The ability of PDSS2 to repress gelsolin might contribute to its tumor-suppressing activity. However, PDSS2 did not influence the sensitivity of the lung cancer cells to chemotherapeutic drugs. Taken together, PDSS2 has tumor-suppressing activity in human lung cancer cells by enhancing apoptosis and inhibiting tumorigenic capacity.
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Kanda M, Nomoto S, Oya H, Hashimoto R, Takami H, Shimizu D, Sonohara F, Kobayashi D, Tanaka C, Yamada S, Fujii T, Nakayama G, Sugimoto H, Koike M, Murotani K, Fujiwara M, Kodera Y. Decreased expression of prenyl diphosphate synthase subunit 2 correlates with reduced survival of patients with gastric cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2014; 33:88. [PMID: 25330808 PMCID: PMC4209044 DOI: 10.1186/s13046-014-0088-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/27/2014] [Accepted: 10/03/2014] [Indexed: 12/21/2022]
Abstract
BACKGROUND Identification of novel molecular biomarkers will improve the management of patients with gastric cancer (GC). Prenyl diphosphate synthase subunit 2 (PDSS2) is required for coenzyme Q10 biosynthesis and acts as a tumor suppressor; however, the role and regulatory mechanisms of PDSS2 in GC are not understood. The aim of this study was to determine expression status and regulatory mechanisms of PDSS2 in GC. METHODS Associations between expression and methylation of PDSS2 were evaluated using GC cell lines. The clinical significance of PDSS2 expression was evaluated using 238 pairs of surgically resected gastric tissues with subgroup analysis based on GC subtypes. RESULTS The expression of PDSS2 mRNA was decreased in 73% of GC cell lines compared with the control non-cancerous cell. The PDSS2 promoter was hypermethylated in cells with decreased PDSS2 expression, and treating these cells with a methylation inhibitor reactivated PDSS2 expression. GC tissues expressed significantly lower mean levels of PDSS2 mRNA compared with adjacent normal tissues (P <0.001). The expression pattern of PDSS2 protein was consistent with that of its mRNA. The decrease of PDSS2 mRNA expression in GC tissues (less than half the level of expression detected in the corresponding normal adjacent tissues) correlated significantly with elevated levels of carbohydrate antigen 19-9 (P = 0.015), lymph node metastasis (P = 0.022), and shorter recurrence-free survival after curative resection (P = 0.022). Further, multivariate analysis identified PDSS2 mRNA expression as an independent prognostic factor (hazard ratio 1.95, 95% confidence interval 1.22-3.09, P = 0.005), and its expression pattern and prognostic significance were similar among three GC subtypes. CONCLUSIONS PDSS2 encodes a putative tumor suppressor, and we show here that its expression was regulated by hypermethylation of its promoter in GC cells. Inhibition of PDSS2 mRNA expression may serve as a novel biomarker of all types of GC.
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Affiliation(s)
- Mitsuro Kanda
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Shuji Nomoto
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Hisaharu Oya
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Ryoji Hashimoto
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Hideki Takami
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Dai Shimizu
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Fuminori Sonohara
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Daisuke Kobayashi
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Chie Tanaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Suguru Yamada
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Tsutomu Fujii
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Goro Nakayama
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Hiroyuki Sugimoto
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Masahiko Koike
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Kenta Murotani
- Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan.
| | - Michitaka Fujiwara
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
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Kanda M, Nomoto S, Oya H, Hashimoto R, Takami H, Shimizu D, Sonohara F, Kobayashi D, Tanaka C, Yamada S, Fujii T, Nakayama G, Sugimoto H, Koike M, Murotani K, Fujiwara M, Kodera Y. Decreased expression of prenyl diphosphate synthase subunit 2 correlates with reduced survival of patients with gastric cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2014. [PMID: 25330808 DOI: 10.1186/preaccept-8549609481376418] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Identification of novel molecular biomarkers will improve the management of patients with gastric cancer (GC). Prenyl diphosphate synthase subunit 2 (PDSS2) is required for coenzyme Q10 biosynthesis and acts as a tumor suppressor; however, the role and regulatory mechanisms of PDSS2 in GC are not understood. The aim of this study was to determine expression status and regulatory mechanisms of PDSS2 in GC. METHODS Associations between expression and methylation of PDSS2 were evaluated using GC cell lines. The clinical significance of PDSS2 expression was evaluated using 238 pairs of surgically resected gastric tissues with subgroup analysis based on GC subtypes. RESULTS The expression of PDSS2 mRNA was decreased in 73% of GC cell lines compared with the control non-cancerous cell. The PDSS2 promoter was hypermethylated in cells with decreased PDSS2 expression, and treating these cells with a methylation inhibitor reactivated PDSS2 expression. GC tissues expressed significantly lower mean levels of PDSS2 mRNA compared with adjacent normal tissues (P <0.001). The expression pattern of PDSS2 protein was consistent with that of its mRNA. The decrease of PDSS2 mRNA expression in GC tissues (less than half the level of expression detected in the corresponding normal adjacent tissues) correlated significantly with elevated levels of carbohydrate antigen 19-9 (P = 0.015), lymph node metastasis (P = 0.022), and shorter recurrence-free survival after curative resection (P = 0.022). Further, multivariate analysis identified PDSS2 mRNA expression as an independent prognostic factor (hazard ratio 1.95, 95% confidence interval 1.22-3.09, P = 0.005), and its expression pattern and prognostic significance were similar among three GC subtypes. CONCLUSIONS PDSS2 encodes a putative tumor suppressor, and we show here that its expression was regulated by hypermethylation of its promoter in GC cells. Inhibition of PDSS2 mRNA expression may serve as a novel biomarker of all types of GC.
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Affiliation(s)
- Mitsuro Kanda
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Shuji Nomoto
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Hisaharu Oya
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Ryoji Hashimoto
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Hideki Takami
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Dai Shimizu
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Fuminori Sonohara
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Daisuke Kobayashi
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Chie Tanaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Suguru Yamada
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Tsutomu Fujii
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Goro Nakayama
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Hiroyuki Sugimoto
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Masahiko Koike
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Kenta Murotani
- Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan.
| | - Michitaka Fujiwara
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
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Kanda M, Sugimoto H, Nomoto S, Oya H, Shimizu D, Takami H, Hashimoto R, Sonohara F, Okamura Y, Yamada S, Fujii T, Nakayama G, Koike M, Fujiwara M, Kodera Y. Clinical utility of PDSS2 expression to stratify patients at risk for recurrence of hepatocellular carcinoma. Int J Oncol 2014; 45:2005-12. [PMID: 25189544 DOI: 10.3892/ijo.2014.2637] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2014] [Accepted: 08/21/2014] [Indexed: 11/06/2022] Open
Abstract
Identification of novel genetic and epigenetic alterations is required for optimal stratification of patients with hepatocellular carcinoma (HCC) at risk for recurrence and adverse prognosis. Coenzyme Q10 (CoQ10), which mediates apoptosis, is synthesized by prenyl diphosphate synthase subunit 2 (PDSS2). In the present study we evaluated the clinical significance and regulatory mechanisms of PDSS2 expression in HCC. PDSS2 expression levels and those of genes encoding potentially interacting proteins as well as the methylation status of the PDSS2 promoter region were analyzed in HCC cell lines. PDSS2 mRNA levels in 151 pairs of resected specimens were determined to evaluate the association of PDSS2 expression and clinicopathological factors. The expression and distribution of PDSS2 were determined using immunohistochemistry. PDSS2 mRNA expression was decreased in six of nine HCC cell lines and significantly correlated with those of hepatocyte nuclear factor 4α. PDSS2 transcription in HCC cells with decreased PDSS2 expression accompanying hypermethylation was reactivated after treating these cells with a methylation inhibitor. Mean expression levels of PDSS2 mRNA relative to that of uninvolved liver diminished gradually in the order of chronic hepatitis to cirrhosis, and each was significantly higher than those of HCCs. PDSS2 and PDSS2 mRNA levels were consistent. Decreased PDSS2 mRNA levels were detected in HCC tissues of 56 patients, correlated with shorter disease-specific survival, and was identified as an independent prognostic factor. PDSS2 is a putative tumor suppressor, and promoter hypermethylation is a key regulatory mechanism in HCC. Decreased levels of PDSS2 mRNA expression may represent a novel biomarker of HCC.
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Affiliation(s)
- Mitsuro Kanda
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroyuki Sugimoto
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shuji Nomoto
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hisaharu Oya
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Dai Shimizu
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hideki Takami
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Ryoji Hashimoto
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Fuminori Sonohara
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yukiyasu Okamura
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Suguru Yamada
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tsutomu Fujii
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Goro Nakayama
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masahiko Koike
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Michitaka Fujiwara
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
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