Predictive value of CPT1A and CPT2 expression levels in prognosis of clear cell renal cell carcinoma

Yiqiang HUANG; Song PENG; Peng TANG; Ze WANG; Jing XU; Qiang MA; Peng ZHONG; Jun ZHANG; Qiuli LIU; Jun JIANG

doi:10.16016/j.2097-0927.202205078

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Predictive value of CPT1A and CPT2 expression levels in prognosis of clear cell renal cell carcinoma

Clinical Medicine | 更新时间：2026-01-09

- Predictive value of CPT1A and CPT2 expression levels in prognosis of clear cell renal cell carcinoma
- Journal of Army Medical University Vol. 45, Issue 1, Pages: 45-53(2023)
- 作者机构：
  
  1.400042 重庆，陆军特色医学中心泌尿外科
  2.400042 重庆，陆军特色医学中心病理科
- 作者简介：
- 基金信息：
  
  the General Program of National Natural Science Foundation of China(81972398);the General Program of National Natural Science Foundation of China(82172807)
- DOI：10.16016/j.2097-0927.202205078
  CLC： R730.43;R730.7;R737.11
- Received：14 May 2022，
  
  Revised：2022-09-13，
  
  Published：15 January 2023
- 稿件说明：
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Yiqiang HUANG, Song PENG, Peng TANG, et al. Predictive value of CPT1A and CPT2 expression levels in prognosis of clear cell renal cell carcinoma[J]. Journal of Army Medical University, 2023, 45(1): 45-53.
DOI：

Yiqiang HUANG, Song PENG, Peng TANG, et al. Predictive value of CPT1A and CPT2 expression levels in prognosis of clear cell renal cell carcinoma[J]. Journal of Army Medical University, 2023, 45(1): 45-53. DOI： 10.16016/j.2097-0927.202205078.

摘要

目的

探索脂肪酸降解相关基因肉碱棕榈酰转移酶IA (carnitine Palmitoyltransferase 1A

CPT1A)和肉碱棕榈酰转移酶Ⅱ(carnitine Palmitoyltransferase 2

CPT2)在肾透明细胞癌(clear cell renal cell carcinoma

ccRCC)的表达及意义。

方法

生物信息学分析癌症基因组图谱(The Cancer Genome Atlas，TCGA)、纪念斯隆·凯特琳癌症中心(Memorial Sloan Kettering Cancer Center，MSKCC)的ccRCC数据中脂肪酸降解相关基因及代谢物。采用免疫组化染色和Western blot分析脂肪酸降解关键基因CPT1A、CPT2蛋白表达水平。构建ccRCC组织芯片(

=103)，通过CPT1A、CPT2免疫组化染色评分分析二者表达和预后的关系。构建并初步评价预后预测模型。

结果

生物信息学分析结果显示，CPT1A、CPT2是参与棕榈酰肉碱代谢、脂肪酸氧化及肾癌进展的关键基因。组织芯片和TCGA队列的结果显示：(1)ccRCC中CPT1A和CPT2的表达水平均较正常肾组织降低(

0.05)；(2)免疫组化评分显示CPT1A、CPT2的表达与病理分级(

=-0.243，

=0.013；

=-0.391

0.01)和TNM分期(

=-0.363

0.01；

=-0.430

0.01)负相关；(3)CPT1A、CPT2低表达与较低的无疾病生存率相关(

0.01)。Cox回归分析结果显示，CPT2表达水平是ccRCC独立预后因素(

0.01)。T

NM-CPT1A、TNM-CPT2预后模型能显著提高TNM分期对预后的预测能力。

结论

与高表达患者相比，CPT1A、CPT2低表达预示ccRCC患者预后不良。

Abstract

Objective

To explore the expressions of fatty acid degradation related genes carnitine palmitoyltransferase 1A (CPT1A) and carnitine palmitoyltransferase 2 (CPT2) in clear cell renal cell carcinoma (ccRCC) and their prognostic significance.

Methods

The genes involved in fatty acid degradation and their related metabolites in the ccRCC datasets from The Cancer Genome Atlas (TCGA) and Memorial Sloan Kettering Cancer Center (MSKCC) were analyzed by bioinformatic tools. Clinical data of renal carcinoma patients admitted to our hospital from 2007 to 2016 were collected. Immunohistochemical (IHC) staining and Western blotting were performed to detect the levels of CPT1A and CPT2

key genes of fatty acid degradation. The tissue chips of ccRCC were prepared (

=103)

and IHC scores of CPT1A and CPT2 were used to estimate the relationship between their expression and prognosis of patients. Subsequently

the prognostic models were constructed and preliminarily evaluated.

Results

Bioinformatics analysis revealed that CPT1A and CPT2 were key genes involved in palmitylcarnitine metabolism

fatty acid oxidation and renal carcinoma progression. The results of tissue microarray and TCGA cohort showed that ①The expression levels of both CPT1A and CPT2 in ccRCC were lower than those in normal renal tissues (

0.05); ②IHC scores indicated that the expression levels of CPT1A and CPT2 were negatively correlated with pathological grade (

=-0.243

=0.013;

=-0.391

0.01) as well as with TNM stage

(

=-0.363

0.01;

=-0.430

0.01); ③Reduced levels of CPT1A a

nd CPT2 were associated with declined disease-free survival (

0.01). Moreover

Cox regression analysis showed that CPT2 expression level was an independent prognostic factor for ccRCC patients (

0.01). Finally

TNM-CPT1A and TNM-CPT2 models significantly improved the ability of TNM stage alone to predict ccRCC prognosis.

Conclusion

Compared with patients with high expression

low expression of CPT1A and CPT2 predicted poor prognosis in patients with ccRCC.

关键词

Keywords

references

BARATA P C, RINI B I. Treatment of renal cell carcinoma: current status and future directions[J]. CA Cancer J Clin, 2017, 67(6): 507-524. DOI:10.3322/caac.21411.

CHEN W Q, ZHENG R S, BAADE P D, et al . Cancer statistics in China, 2015[J ] . CA A Cancer J Clin, 2016, 66(2): 115-132. DOI:10.3322/caac.21338.

LJUNGBERG B, ALBIGES L, ABU-GHANEM Y, et al . European Association of Urology guidelines on renal cell carcinoma: the 2019 update[J ] . Eur Urol, 2019, 75(5): 799-810. DOI:10.1016/j.eururo.2019.02.011.

HSIEH J J, LE V H, OYAMA T, et al . Chromosome 3p loss-orchestrated VHL, HIF, and epigenetic deregulation in clear cell renal cell carcinoma[J ] . J Clin Oncol, 2018, 36(36): JCO2018792549. DOI:10.1200/JCO.2018.79.2549.

KOUNDOUROS N, POULOGIANNIS G. Reprogramming of fatty acid metabolism in cancer[J]. Br J Cancer, 2020, 122(1): 4-22. DOI:10.1038/s41416-019-0650-z.

MELONE M A B, VALENTINO A, MARGARUCCI S, et al . The carnitine system and cancer metabolic plasticity[J ] . Cell Death Dis, 2018, 9(2): 228. DOI:10.1038/s41419-018-0313-7.

BONNEFONT J P, DJOUADI F, PRIP-BUUS C, et al . Carnitine palmitoyltransferases 1 and 2: biochemical, molecular and medical aspects[J ] . Mol Aspects Med, 2004, 25(5/6): 495-520. DOI:10.1016/j.mam.2004.06.004.

IWAMOTO H, ABE M, YANG Y L, et al . Cancer lipid metabolism confers antiangiogenic drug resistance[J ] . Cell Metab, 2018, 28(1): 104-117. e5. DOI:10.1016/j.cmet.2018.05.005.

HAKIMI A A, REZNIK E, LEE C H, et al . An integrated metabolic atlas of clear cell renal cell carcinoma[J ] . Cancer Cell, 2016, 29(1): 104-116. DOI:10.1016/j.ccell.2015.12.004.

CHANDRASHEKAR D S, BASHEL B, BALASUBRA-MANYA S A H, et al . UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses[J ] . Neoplasia, 2017, 19(8): 649-658. DOI:10.1016/j.neo.2017.05.002.

AIDERUS A, BLACK M A, DUNBIER A K. Fatty acid oxidation is associated with proliferation and prognosis in breast and other cancers[J]. BMC Cancer, 2018, 18(1): 805. DOI:10.1186/s12885-018-4626-9.

KALLIONIEMI O P, WAGNER U, KONONEN J, et al . Tissue microarray technology for high-throughput molecular profiling of cancer[J ] . Hum Mol Genet, 2001, 10(7): 657-662. DOI:10.1093/hmg/10.7.657.

WETTERSTEN H I, HAKIMI A A, MORIN D, et al . Grade-dependent metabolic reprogramming in kidney cancer revealed by combined proteomics and metabolomics analysis[J ] . Cancer Res, 2015, 75(12): 2541-2552. DOI:10.1158/0008-5472.CAN-14-1703.

GANTI S L, TAYLOR S L, KIM K, et al . Urinary acylcarnitines are altered in human kidney cancer[J ] . Int J Cancer, 2012, 130(12): 2791-2800. DOI:10.1002/ijc.26274.

DU W N, ZHANG L C, BRETT-MORRIS A, et al . HIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism[J ] . Nat Commun, 2017, 8(1): 1769. DOI:10.1038/s41467-017-01965-8.

HERAVI G, YAZDANPANAH O, PODGORSKI I, et al . Lipid metabolism reprogramming in renal cell carcinoma[J ] . Cancer Metastasis Rev, 2022, 41(1): 17-31. DOI:10.1007/s10555-021-09 996-w.

YANG H, ZHAO H, REN Z, et al . Overexpression CPT1A reduces lipid accumulation via PPARα/CD36 axis to suppress the cell proliferation in ccRCC[J ] . Acta Biochim Biophys Sin (Shanghai), 2022, 54(2): 220-231. DOI:10.3724/abbs.2021023..

LU W Q, CHE X F, QU X J, et al . Succinylation regulators promote clear cell renal cell carcinoma by immune regulation and RNA N6-methyladenosine methylation[J ] . Front Cell Dev Biol, 2021, 9: 622198. DOI:10.3389/fcell.2021.622198.

LU X, ZHANG X H, ZHANG Y J, et al . Metabolic profiling analysis upon acylcarnitines in tissues of hepatocellular carcinoma revealed the inhibited carnitine shuttle system caused by the downregulated carnitine palmitoyltransferase 2[J ] . Mol Carcinog, 2019, 58(5): 749-759. DOI:10.1002/mc.22967.

LIU F Q, LI X Q, YAN H, et al . Downregulation of CPT2 promotes proliferation and inhibits apoptosis through p53 pathway in colorectal cancer[J ] . Cell Signal, 2022, 92: 110267. DOI:10.1016/j.cellsig.2022.110267.

LI H, CHEN J H, LIU J, et al . CPT2 downregulation triggers stemness and oxaliplatin resistance in colorectal cancer via activating the ROS/Wnt/β-catenin-induced glycolytic metabolism[J ] . Exp Cell Res, 2021, 409(1): 112892. DOI:10.1016/j.yexcr.2021.112892..

FUJIWARA N, NAKAGAWA H, ENOOKU K, et al . CPT2 downregulation adapts HCC to lipid-rich environment and promotes carcinogenesis via acylcarnitine accumulation in obesity[J ] . Gut, 2018, 67(8): 1493-1504. DOI:10.1136/gutjnl-2017-315193..

LIN M H, LV D, ZHENG Y L, et al . Downregulation of CPT2 promotes tumorigenesis and chemoresistance to cisplatin in hepatocellular carcinoma[J ] . OncoTargets Ther, 2018, 11: 3101-3110. DOI:10.2147/OTT.S163266.

ZHANG X H, ZHANG Z, LIU S J, et al . CPT2 down-regulation promotes tumor growth and metastasis through inducing ROS/NFκB pathway in ovarian cancer[J ] . Transl Oncol, 2021, 14(4): 101023. DOI:10.1016/j.tranon.2021.101023.

VAN DER MIJN J C, FU L P, KHANI F, et al . Combined metabolomics and genome-wide transcriptomics analyses show multiple HIF1α-induced changes in lipid metabolism in early stage clear cell renal cell carcinoma[J ] . Transl Oncol, 2020, 13(2): 177-185. DOI:10.1016/j.tranon.2019.10.015.

TAMAYO P, CHO Y J, TSHERNIAK A, et al . Predicting relapse in patients with medulloblastoma by integrating evidence from clinical and genomic features[J ] . J Clin Oncol, 2011, 29(11): 1415-1423. DOI:10.1200/JCO.2010.28.1675.

PARKER W P, CHEVILLE J C, FRANK I, et al . Application of the stage, size, grade, and necrosis (SSIGN) score for clear cell renal cell carcinoma in contemporary patients[J ] . Eur Urol, 2017, 71(4): 665-673. DOI:10.1016/j.eururo.2016.05.034.

BLACKMUR J P, GABA F, FERNANDO D, et al . Leibovich score is the optimal clinico-pathological system associated with recurrence of non-metastatic clear cell renal cell carcinoma[J ] . Urol Oncol, 2021, 39(7): 438. e11-438.438. e21. DOI:10.1016/j.urolonc.2021.04.007.

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