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1
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Zou Z, Chai Y, Li Q, Lin X, He Q, Xiong Q. Establishment of lactate-metabolism-related signature to predict prognosis and immunotherapy response in patients with colon adenocarcinoma. Front Oncol 2022; 12:958221. [PMID: 36185199 PMCID: PMC9515658 DOI: 10.3389/fonc.2022.958221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 07/25/2022] [Indexed: 11/13/2022] Open
Abstract
The outcome of colon adenocarcinoma (COAD) patients remains dismal, and lactate metabolism has been characterized to promote tumor development and immune evasion. Based on the above background, it is worthwhile to explore novel prognostic and therapeutic biomarkers for COAD patients from the aspect of lactate metabolism. Above all, 228 available lactate-metabolism-related genes (LMRGs) were acquired, and the landscape of copy number variation and the expression difference of mRNA levels between colon normal and tumor samples were investigated among these LMRGs. Importantly, eight overall survival (OS)-involved LMRGs were then distinguished by means of univariate Cox regression analysis in both GSE40967 and TCGA-COAD data sets. Subsequently, prognostic risk scores were established, integrating seven OS-related LMRGs by LASSO Cox regression analysis in the GSE40967 set, and then verified in the TCGA-COAD cohort. From the comprehensive analyses, COAD patients with high risk had comparatively more inferior survival probability in all populations of the study, and they tended to have more severe clinicopathological features with the risk score increasing. Moreover, by integrating age, AJCC T and pathological stage, and risk score, we constructed a prognostic nomogram that demonstrated great prediction effectiveness for OS of COAD patients. Furthermore, the potential effect of various risk score on tumor immune was assessed from enrichment of immune-related pathways, tumor-infiltrating immune cells, and expression levels of immune checkpoints separately. We could draw a conclusion that COAD patients with higher lactate-metabolism-related risk scores may acquire an immunosuppressive tumor microenvironment, which subsequently led to immune escapes and poor prognoses. Conclusively, all findings in the present study illustrate a great prognostic value of the lactate-metabolism-related risk signature, providing more in-depth insights into the indispensable function of lactate metabolism in prognosis and tumor immunity of COAD.
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Affiliation(s)
- Zhengrong Zou
- Department of Emergency Trauma Center, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Yongjie Chai
- Department of Anorectal Surgery, Zhucheng People’s Hospital, Zhucheng, China
| | - Qi Li
- Basic Medicine Department of Chuxiong Medical and Pharmaceutical College, Chuxiong, China
| | - Xuan Lin
- Department of Emergency Trauma Center, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Qingfang He
- Department of General Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Qiusheng Xiong
- Department of General Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- *Correspondence: Qiusheng Xiong,
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2
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Zeng T, Tang Z, Liang L, Suo D, Li L, Li J, Yuan Y, Guan XY, Li Y. PDSS2-Del2, a new variant of PDSS2, promotes tumor cell metastasis and angiogenesis in hepatocellular carcinoma via activating NF-κB. Mol Oncol 2020; 14:3184-3197. [PMID: 33064899 PMCID: PMC7718950 DOI: 10.1002/1878-0261.12826] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 09/08/2020] [Accepted: 09/25/2020] [Indexed: 12/28/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is among the leading causes of cancer‐related mortality worldwide. Our previous study identified a novel alternative splicing variant of prenyl diphosphate synthase subunit 2 (PDSS2) in HCC characterized by a deletion of exon 2, named PDSS2‐Del2, which is devoid of the tumor‐suppressive function of full‐length PDSS2 (PDSS2‐FL). To better understand the clinical significance of PDSS2‐Del2, we performed a BaseScope™ assay on an HCC tissue microarray and found that positive staining for PDSS2‐Del2 predicted a worse overall survival in patients with HCC (P = 0.02). PDSS2‐Del2 levels correlated significantly with microvessel counts in HCC tumor tissues. Importantly, PDSS2‐Del2 overexpression functionally promoted HCC metastasis, as demonstrated by in vitro and in vivo migration assays. In vivo assays also demonstrated that PDSS2‐Del2 increased angiogenesis in xenografts. Furthermore, we discovered that elevated PDSS2‐Del2 expression in HCC tumor cells decreased fumarate levels and activated the canonical nuclear factor‐κB pathway. The epithelial‐to‐mesenchymal transition (EMT) and WNT/β‐catenin signaling pathways were also activated by overexpression. Dimethyl fumarate (DMF), a fumaric acid ester, effectively reduced the metastasis induced by PDSS2‐Del2 as observed with in vivo spleen‐liver metastasis animal experiments. DMF is a prescribed oral therapy for multiple sclerosis and it might be a potential treatment for metastasis of patients with HCC. Early clinical trials are needed to validate its potential in this context.
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Affiliation(s)
- Tingting Zeng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Zhi Tang
- School of Public Health, Guangdong Medical University, Dongguan, China
| | - Lili Liang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Daqin Suo
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Lei Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Clinical Oncology, The University of Hong Kong, China
| | - Jiangchao Li
- Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yunfei Yuan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xin-Yuan Guan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,Department of Clinical Oncology, The University of Hong Kong, China
| | - Yan Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
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3
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Zhao L. Mitochondrial DNA degradation: A quality control measure for mitochondrial genome maintenance and stress response. Enzymes 2019; 45:311-341. [PMID: 31627882 DOI: 10.1016/bs.enz.2019.08.004] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Mitochondria play a central role in bioenergetics, and fulfill a plethora of functions in cell signaling, programmed cell death, and biosynthesis of key protein cofactors. Mitochondria harbor their own genomic DNA, which encodes protein subunits of the electron transport chain and a full set of transfer and ribosomal RNAs. Mitochondrial DNA (mtDNA) is essential for cellular and organismal functions, and defects in mitochondrial genome maintenance have been implicated in common human diseases and mitochondrial disorders. mtDNA repair and degradation are known pathways to cope with mtDNA damage; however, molecular factors involved in this process have remained unclear. Such knowledge is fundamental to the understanding of mitochondrial genomic maintenance and pathology, because mtDNA degradation may contribute to the etiology of mtDNA depletion syndromes and to the activation of the innate immune response by fragmented mtDNA. This article reviews the current literature regarding the importance of mitochondrial DNA degradation in mtDNA maintenance and stress response, and the recent progress in uncovering molecular factors involved in mtDNA degradation. These factors include key components of the mtDNA replication machinery, such as DNA polymerase γ, helicase Twinkle, and exonuclease MGME1, as well as a major DNA-packaging protein, mitochondrial transcription factor A (TFAM).
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Affiliation(s)
- Linlin Zhao
- Department of Chemistry, University of California, Riverside, Riverside, CA, United States.
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4
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Li Y, Lin S, Li L, Tang Z, Hu Y, Ban X, Zeng T, Zhou Y, Zhu Y, Gao S, Deng W, Zhang X, Xie D, Yuan Y, Huang P, Li J, Cai Z, Guan XY. PDSS2 Deficiency Induces Hepatocarcinogenesis by Decreasing Mitochondrial Respiration and Reprogramming Glucose Metabolism. Cancer Res 2018; 78:4471-4481. [PMID: 29967258 DOI: 10.1158/0008-5472.can-17-2172] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 12/12/2017] [Accepted: 06/19/2018] [Indexed: 11/16/2022]
Abstract
Glucose metabolic reprogramming from oxidative phosphorylation to glycolysis is one of the hallmarks of cancer development. Coenzyme Q10 (CoQ10) is essential for electron transport in the mitochondrial respiratory chain and for antioxidant defense. Here, we investigated the role of a key factor in CoQ10 synthesis, prenyldiphosphate synthase subunit 2 (PDSS2), in hepatocellular carcinoma (HCC) tumorigenesis. PDSS2 was frequently downregulated in HCC tissues and was significantly associated with poorer HCC prognosis (P = 0.027). PDSS2 downregulation was a prognostic factor independent of T status and stage (P = 0.028). Downregulation of CoQ10 was significantly correlated with downregulation of PDSS2 in HCC tumor tissues (R = 0.414; P < 0.001). Of the six different splicing isoforms of PDSS2, the five variants other than full-length PDSS2 showed loss of function in HCC. Reintroduction of full-length PDSS2 into HCC cells increased CoQ10 and mitochondrial electron transport complex I activity and subsequently induced a metabolic shift from aerobic glycolysis to mitochondrial respiration in cells. Reintroduction of PDSS2 also inhibited foci formation, colony formation in soft agar, and tumor formation in nude mice. Knockdown of PDSS2 induced chromosomal instability in the MIHA immortalized human liver cell line. Furthermore, knockdown of PDSS2 in MIHA induced malignant transformation. Overall, our findings indicate that PDSS2 deficiency might be a novel driving factor in HCC development.Significance: Downregulation of PDSS2 is a driving factor in hepatocellular carcinoma tumorigenesis. Cancer Res; 78(16); 4471-81. ©2018 AACR.
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Affiliation(s)
- Yan Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
| | - Shuhai Lin
- State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong, China
| | - Lei Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Zhi Tang
- State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong, China
| | - Yumin Hu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xiaojiao Ban
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Tingting Zeng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ying Zhou
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yinghui Zhu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Song Gao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Wen Deng
- Department of Anatomy, The University of Hong Kong, Hong Kong, China
| | - Xiaoshi Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Dan Xie
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yunfei Yuan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Peng Huang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jinjun Li
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai, China
| | - Zongwei Cai
- State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong, China
| | - Xin-Yuan Guan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. .,Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China
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5
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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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6
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Liu J, Li H, Zhou B, Xu L, Kang X, Yang W, Wu S, Sun H. PGRN induces impaired insulin sensitivity and defective autophagy in hepatic insulin resistance. Mol Endocrinol 2015; 29:528-41. [PMID: 25664864 DOI: 10.1210/me.2014-1266] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Progranulin (PGRN) has recently emerged as an important regulator for glucose metabolism and insulin sensitivity. However, the underlying mechanisms of PGRN in the regulation of insulin sensitivity and autophagy remain elusive. In this study, we aimed to address the direct effects of PGRN in vivo and to evaluate the potential interaction of impaired insulin sensitivity and autophagic disorders in hepatic insulin resistance. We found that mice treated with PGRN for 21 days exhibited the impaired glucose tolerance and insulin tolerance and hepatic autophagy imbalance as well as defective insulin signaling. Furthermore, treatment of mice with TNF receptor (TNFR)-1 blocking peptide-Fc, a TNFR1 blocking peptide-Fc fusion protein to competitively block the interaction of PGRN and TNFR1, resulted in the restoration of systemic insulin sensitivity and the recovery of autophagy and insulin signaling in liver. Consistent with these findings in vivo, we also observed that PGRN treatment induced defective autophagy and impaired insulin signaling in hepatocytes, with such effects being drastically nullified by the addition of TNFR1 blocking peptide -Fc or TNFR1-small interference RNA via the TNFR1-nuclear factor-κB-dependent manner, indicating the causative role of PGRN in hepatic insulin resistance. In conclusion, our findings supported the notion that PGRN is a key regulator of hepatic insulin resistance and that PGRN may mediate its effects, at least in part, by inducing defective autophagy via TNFR1/nuclear factor-κB.
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Affiliation(s)
- Jiali Liu
- First Affiliated Hospital of the Medical School of Xi'an Jiaotong University, and Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
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7
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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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8
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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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9
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Decrease of PDSS2 expression, a novel tumor suppressor, in non-small cell lung cancer. Cancer Epidemiol 2013; 37:166-71. [PMID: 23312889 DOI: 10.1016/j.canep.2012.12.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2012] [Revised: 12/04/2012] [Accepted: 12/09/2012] [Indexed: 01/01/2023]
Abstract
BACKGROUND Prenyl diphosphate synthase subunit 2 (PDSS2) gene has recently been reported as a potential tumor suppressor. The association of PDSS2 and non-small cell lung cancer (NSCLC) has not been known. METHODS To investigate its association with NSCLC, we examined the expression level of PDSS2 in 28 paired clinical samples of non-small cell lung cancer tissues and surrounding normal tissues. RESULTS PDSS2 was constitutionally expressed in normal lung tissues regardless of sex, race and smoking history. An overall decreased PDSS2 expression was found in the tumor tissues compared to surrounding normal tissues. Decrease in PDSS2 expression was more severe in poorly and poor-to-moderately differentiated lung cancers, while the decrease was not significant in moderately to well-differentiated tumors. Moreover, the expression of PDSS2 decreased more in higher pathological stage, and in patients with lymph node metastasis. The decrease in PDSS2 expression in tumor tissues was not related to sex or histological type of NSCLC, but was related to smoking history. No correlation has been found between PDSS2 and the clinical factors of EGRF, Ki-67 and p53. CONCLUSION Taken together, decreased expression of PDSS2 in NSCLC was evident. This is an initial report for the expression of PDSS2 in relation to different factors in lung cancer. Loss of PDSS2 could serve as a potential biomarker in NSCLC development. The role of PDSS2 as a tumor suppressor, and the mechanism of its potential anti-tumor action in NSCLC warrant further investigation.
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