结直肠癌中DPD与LC3、P62表达的相关性及其临床意义

贾真真; 何双; 李扬扬; 温菲菲; 许晓阳; 郭宁杰; 吴淑华

doi:10.19401/j.cnki.1007-3639.2022.01.003

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结直肠癌中DPD与LC3、P62表达的相关性及其临床意义

论著 | 更新时间：2025-12-31

- 结直肠癌中DPD与LC3、P62表达的相关性及其临床意义
- Correlations between expressions of DPD, LC3 and P62 in colorectal cancer and their clinical significance
- 中国癌症杂志 2022年32卷第1期页码：24-33
- 作者机构：
  
  滨州医学院附属医院病理科,山东滨州 256600
- 作者简介：
  
  吴淑华 E-mail: wsh6108@126.com
- 基金信息：
  
  国家自然科学基金(81772637)
- DOI：10.19401/j.cnki.1007-3639.2022.01.003
  中图分类号： R735.3+5;R735.3+7
- 收稿：2021-07-13，
  
  修回：2021-12-02，
  
  纸质出版：2022-01-30
- 稿件说明：
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贾真真, 何双, 李扬扬, 等. 结直肠癌中DPD与LC3、P62表达的相关性及其临床意义[J]. 中国癌症杂志, 2022,32(1):24-33.

Zhenzhen JIA, Shuang HE, Yangyang LI, et al. Correlations between expressions of DPD, LC3 and P62 in colorectal cancer and their clinical significance[J]. China Oncology, 2022, 32(1): 24-33.
贾真真, 何双, 李扬扬, 等. 结直肠癌中DPD与LC3、P62表达的相关性及其临床意义[J]. 中国癌症杂志, 2022,32(1):24-33. DOI： 10.19401/j.cnki.1007-3639.2022.01.003.

Zhenzhen JIA, Shuang HE, Yangyang LI, et al. Correlations between expressions of DPD, LC3 and P62 in colorectal cancer and their clinical significance[J]. China Oncology, 2022, 32(1): 24-33. DOI： 10.19401/j.cnki.1007-3639.2022.01.003.

摘要

背景与目的：

结直肠癌是常见的消化系统恶性肿瘤之一

应用5-氟尿嘧啶（5-fluorouracil

5-FU）治疗结直肠癌常因耐药或不良反应影响其疗效

二氢嘧啶脱氢酶（dihydropyrimidine dehydrogenase

DPD）是5-FU代谢的关键酶

其表达量或降解率可能成为影响5-FU疗效的因素

自噬是细胞内蛋白质降解的重要途径。检测结直肠癌中自噬关键因子微管相关蛋白轻链3（light chain 3

LC3）、P62和DPD的表达

探讨其相关性及临床意义

为逆转5-FU耐药提供新思路。

方法：

采用免疫组织化学EnVision法检测2013

#x02014;2014年滨州医学院附属医院病理科存档的157例结直肠癌石蜡包埋组织

采用蛋白质印迹法（Western blot）及实时荧光定量聚合酶链反应（real-time fluorescence quantitative polymerase chain reaction

RTFQ-PCR）检测2020年滨州医学院附属医院病理科接收的44例结直肠癌新鲜组织中LC3、P62和DPD的表达

分析其相关性及其临床意义。

结果：

结直肠癌组织中LC3、P62和DPD的mRNA及蛋白表达量均高于正常黏膜组织（

0.05）。P62与DPD的表达呈正相关

LC3与P62、DPD的表达均呈负相关（

0.05）。P62

–

/LC3

–

组中DPD蛋白表达量明显高于其他3组

而P62

–

/LC3

组中DPD蛋白表达量则低于其他3组（

0.05）。P62

/LC3

–

组与P62

/LC3

组中DPD蛋白表达量虽不同

但差异无统计学意义（

0.05）。结直肠癌中P62蛋白表达与T分期及淋巴结转移呈正相关;LC3蛋白表达与肿瘤直径及T分期呈正相关;DPD蛋白表达则与组织学类型密切相关（

0.05）。LC3、P62、DPD及淋巴结转移与结直肠癌患者预后密切相关

四者均是结直肠癌患者预后的独立危险因素。

结论：

LC3和P62可影响DPD的表达

自噬-溶酶体途径可能是DPD降解的重要途径

其有可能通过DPD降解进而影响结直肠癌对5-FU的耐药。

Abstract

Background and purpose:

Colorectal cancer is one of the most common malignancies. The efficacy of 5-fluorouracil (5-FU) in the treatment of colorectal cancer is often affected by drug resistance or toxic side effects. Dihydropyrimidine dehydrogenase (DPD) is the key enzyme in the metabolism of 5-FU

and the expression or degradation rate of 5-FU may be a factor affecting the efficacy of 5-FU. Autophagy is an important pathway of intracellular protein degradation. This study aimed to detect the expression of microtubule-associated protein light chain 3 (LC3)

P62 and DPD in colorectal cancer

and to explore their correlation and clinical significance

so as to provide a new way to reverse 5-FU resistance.

Methods:

Immunohistochemical envision method was used to detect the expressions of LC3

p62 and DPD in 157 colorectal cancer paraffin tissues archived by Department of Pathology

Binzhou Medical University Hospital from 2013 to 2014. Western blot and real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR) were used to detect the expressions of LC3

p62 and DPD in 44 colorectal cancer fresh tissues received by Department of Pathology

Binzhou Medical University Hospital in 2020. The correlation and clinical significance were analyzed.

Results:

The expressions of LC3

P62 and DPD were significantly higher in colorectal carcinoma than in normal tissues (

0.05). The expressions of P62 was positively correlated with the expressions of DPD

and the expressions of LC3 was negatively correlated with the expressions of P62 and DPD (

0.05). The expression of DPD was significantly higher in P62

/LC3

group than in the other three groups

while the expression of DPD was significantly lower in P62

/LC3

group than in the other three groups (P

0.05). The protein expression of DPD in P62

/LC3

and P62

/LC3

group were different

but the difference was not statistically significant (

0.05). The expression of P62 was positively correlated with T stage and lymph node metastasis. The expression of LC3 was positively correlated with tumor size and T stage. The protein expression of DPD was closely related to histological type (

0.05). LC3

P62

DPD and lymph node metastasis were related to the prognosis of colorectal cancer patients. All of them were independent risk factors for the prognosis of colorectal cancer.

Conclusion:

LC3 and p62 can affect the expression of DPD. Autophagy-lysosome pathway may be an important pathway of DPD degradation

which may affect the resistance of colorectal cancer to 5-FU through the degradation rate of DPD.

关键词

Keywords

references

CHEN W Q , LI H , SUN K X , et al. Report of cancer incidence and mortality in China, 2014 [J ] . Chin J Oncol , 2018 , 40 ( 1 ): 5 - 13 .

BENSON A B , VENOOK A P , AL-HAWARY M M , et al. NCCN guidelines insights: colon cancer, version 2.2018 [J ] . J Natl Compr Canc Netw , 2018 , 16 ( 4 ): 359 - 369 . DOI: 10.6004/jnccn.2018.0021 http://doi.org/10.6004/jnccn.2018.0021 https://jnccn.org/doi/10.6004/jnccn.2018.0021 https://jnccn.org/doi/10.6004/jnccn.2018.0021

LIN K , JIANG H , ZHUANG S S , et al. Long noncoding RNA LINC00261 induces chemosensitization to 5-fluorouracil by mediating methylation-dependent repression of DPYD in human esophageal cancer [J ] . FASEB J , 2019 , 33 ( 2 ): 1972 - 1988 . DOI: 10.1096/fsb2.v33.2 http://doi.org/10.1096/fsb2.v33.2 https://onlinelibrary.wiley.com/toc/15306860/33/2 https://onlinelibrary.wiley.com/toc/15306860/33/2

CHEN L J , SHE X D , WANG T , et al. Overcoming acquired drug resistance in colorectal cancer cells by targeted delivery of 5-FU with EGF grafted hollow mesoporous silica nanoparticles [J ] . Nanoscale , 2015 , 7 ( 33 ): 14080 - 14092 . DOI: 10.1039/C5NR03527A http://doi.org/10.1039/C5NR03527A http://xlink.rsc.org/?DOI=C5NR03527A http://xlink.rsc.org/?DOI=C5NR03527A

SHARMA V , GUPTA S K , VERMA M . Dihydropyrimidine dehydrogenase in the metabolism of the anticancer drugs [J ] . Cancer Chemother Pharmacol , 2019 , 84 ( 6 ): 1157 - 1166 . DOI: 10.1007/s00280-019-03936-w http://doi.org/10.1007/s00280-019-03936-w https://doi.org/10.1007/s00280-019-03936-w https://doi.org/10.1007/s00280-019-03936-w

CHAMOREY E , FRANCOIS E , ETIENNE M C , et al. DPD status and fluoropyrimidines-based treatment: high activity matters too [J ] . BMC Cancer , 2020 , 20 ( 1 ): 436 . DOI: 10.1186/s12885-020-06907-0 http://doi.org/10.1186/s12885-020-06907-0 https://doi.org/10.1186/s12885-020-06907-0 https://doi.org/10.1186/s12885-020-06907-0

ZHANG Y H , LUO D D , WAN S B , et al. S1PR2 inhibitors potently reverse 5-FU resistance by downregulating DPD expression in colorectal cancer [J ] . Pharmacol Res , 2020 , 155 : 104717 . DOI: 10.1016/j.phrs.2020.104717 http://doi.org/10.1016/j.phrs.2020.104717 https://linkinghub.elsevier.com/retrieve/pii/S1043661819324934 https://linkinghub.elsevier.com/retrieve/pii/S1043661819324934

SHEN X M , ZHOU C , LIAN L , et al. Relationship between the DPD and TS mRNA expression and the response to S-1-based chemotherapy and prognosis in patients with advanced gastric cancer [J ] . Cell Biochem Biophys , 2015 , 71 ( 3 ): 1653 - 1661 . DOI: 10.1007/s12013-014-0387-5 http://doi.org/10.1007/s12013-014-0387-5 http://link.springer.com/10.1007/s12013-014-0387-5 http://link.springer.com/10.1007/s12013-014-0387-5

MAGNES T , MELCHARDT T , WEISS L , et al. Fluorouracil and dihydropyrimidine dehydrogenase genotyping [J ] . J Clin Oncol , 2016 , 34 ( 20 ): 2433 - 2434 . DOI: 10.1200/JCO.2016.66.6057 http://doi.org/10.1200/JCO.2016.66.6057 https://ascopubs.org/doi/10.1200/JCO.2016.66.6057 https://ascopubs.org/doi/10.1200/JCO.2016.66.6057

ZHANG Y H , SHI W N , WU S H , et al. SphK2 confers 5-fluorouracil resistance to colorectal cancer via upregulating H3K56ac-mediated DPD expression [J ] . Oncogene , 2020 , 39 ( 29 ): 5214 - 5227 . DOI: 10.1038/s41388-020-1352-y http://doi.org/10.1038/s41388-020-1352-y https://doi.org/10.1038/s41388-020-1352-y https://doi.org/10.1038/s41388-020-1352-y

YANG C G , CICCOLINI J , BLESIUS A , et al. DPD-based adaptive dosing of 5-FU in patients with head and neck cancer: impact on treatment efficacy and toxicity [J ] . Cancer Chemother Pharmacol , 2011 , 67 ( 1 ): 49 - 56 . DOI: 10.1007/s00280-010-1282-4 http://doi.org/10.1007/s00280-010-1282-4 http://link.springer.com/10.1007/s00280-010-1282-4 http://link.springer.com/10.1007/s00280-010-1282-4

TAKECHI T , FUJIOKA A , MATSUSHIMA E , et al. Enhancement of the antitumour activity of 5-fluorouracil (5-FU) by inhibiting dihydropyrimidine dehydrogenase activity (DPD) using 5-chloro-2, 4-dihydroxypyridine (CDHP) in human tumour cells [J ] . Eur J Cancer , 2002 , 38 ( 9 ): 1271 - 1277 . DOI: 10.1016/S0959-8049(02)00048-5 http://doi.org/10.1016/S0959-8049(02)00048-5 https://linkinghub.elsevier.com/retrieve/pii/S0959804902000485 https://linkinghub.elsevier.com/retrieve/pii/S0959804902000485

刘柳 , 吴淑华 , 李扬扬 , 等 . 结直肠癌中HSF1、c-Jun与DPD表达的相关性及其临床意义 [J ] . 临床与实验病理学杂志 , 2020 , 36 ( 11 ): 1261 - 1268 .

LIU L , WU S H , LI Y Y , et al. Correlation of HSF1, c-Jun and DPD expression in colorectal adenocarcinoma and their clinical significance [J ] . Chin J Clin Exp Pathol , 2020 , 36 ( 11 ): 1261 - 1268 .

NAM T , HAN J H , DEVKOTA S , et al. Emerging paradigm of crosstalk between autophagy and the ubiquitin-proteasome system [J ] . Mol Cells , 2017 , 40 ( 12 ): 897 - 905 .

LEVINE B , KROEMER G . Biological functions of autophagy genes: a disease perspective [J ] . Cell , 2019 , 176 ( 1/2 ): 11 - 42 . DOI: 10.1016/j.cell.2018.09.048 http://doi.org/10.1016/j.cell.2018.09.048 https://linkinghub.elsevier.com/retrieve/pii/S0092867418312601 https://linkinghub.elsevier.com/retrieve/pii/S0092867418312601

MOORS T E , HOOZEMANS J J , INGRASSIA A , et al. Therapeutic potential of autophagy-enhancing agents in Parkinson’s disease [J ] . Mol Neurodegener , 2017 , 12 ( 1 ): 11 . DOI: 10.1186/s13024-017-0154-3 http://doi.org/10.1186/s13024-017-0154-3 http://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-017-0154-3 http://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-017-0154-3

LI Q , LIU Y , SUN M . Autophagy and Alzheimer’s disease [J ] . Cell Mol Neurobiol , 2017 , 37 ( 3 ): 377 - 388 . DOI: 10.1007/s10571-016-0386-8 http://doi.org/10.1007/s10571-016-0386-8 http://link.springer.com/10.1007/s10571-016-0386-8 http://link.springer.com/10.1007/s10571-016-0386-8

LI Y J , LEI Y H , YAO N , et al. Autophagy and multidrug resistance in cancer [J ] . Chin J Cancer , 2017 , 36 ( 1 ): 52 . DOI: 10.1186/s40880-017-0219-2 http://doi.org/10.1186/s40880-017-0219-2 https://cancercommun.biomedcentral.com/articles/10.1186/s40880-017-0219-2 https://cancercommun.biomedcentral.com/articles/10.1186/s40880-017-0219-2

YANG J W , ZHANG Q H , LIU T . Autophagy facilitates anticancer effect of 5-fluorouracil in HCT-116 cells [J ] . J Cancer Res Ther , 2018 , 14(Suppl): S1141-S1147 .

YAO C W , KANG K A , PIAO M J , et al. Reduced autophagy in 5-fluorouracil resistant colon cancer cells [J ] . Biomol Ther (Seoul) , 2017 , 25 ( 3 ): 315 - 320 . DOI: 10.4062/biomolther.2016.069 http://doi.org/10.4062/biomolther.2016.069 http://www.biomolther.org/journal/DOIx.php?id=10.4062/biomolther.2016.069 http://www.biomolther.org/journal/DOIx.php?id=10.4062/biomolther.2016.069

ISLAM M , SOORO M , ZHANG P H . Autophagic regulation of p62 is critical for cancer therapy [J ] . Int J Mol Sci , 2018 , 19 ( 5 ): 1405 . DOI: 10.3390/ijms19051405 http://doi.org/10.3390/ijms19051405 http://www.mdpi.com/1422-0067/19/5/1405 http://www.mdpi.com/1422-0067/19/5/1405

LAMARK T , SVENNING S , JOHANSEN T . Regulation of selective autophagy: the p62/SQSTM1 paradigm [J ] . Essays Biochem , 2017 , 61 ( 6 ): 609 - 624 . DOI: 10.1042/EBC20170035 http://doi.org/10.1042/EBC20170035 https://portlandpress.com/essaysbiochem/article/61/6/609/78478/Regulation-of-selective-autophagy-the-p62-SQSTM1 https://portlandpress.com/essaysbiochem/article/61/6/609/78478/Regulation-of-selective-autophagy-the-p62-SQSTM1

JIN H , SEO G S , LEE S H . Isoliquiritigenin-mediated p62/SQSTM1 induction regulates apoptotic potential through attenuation of caspase-8 activation in colorectal cancer cells [J ] . Eur J Pharmacol , 2018 , 841 : 90 - 97 . DOI: 10.1016/j.ejphar.2018.10.015 http://doi.org/10.1016/j.ejphar.2018.10.015 https://linkinghub.elsevier.com/retrieve/pii/S0014299918305910 https://linkinghub.elsevier.com/retrieve/pii/S0014299918305910

KUO W L , SHARIFI M N , LINGEN M W , et al. p62/SQSTM1 accumulation in squamous cell carcinoma of head and neck predicts sensitivity to phosphatidylinositol 3-kinase pathway inhibitors [J ] . PLoS One , 2014 , 9 ( 3 ): e90171 . DOI: 10.1371/journal.pone.0090171 http://doi.org/10.1371/journal.pone.0090171 https://dx.plos.org/10.1371/journal.pone.0090171 https://dx.plos.org/10.1371/journal.pone.0090171

PARK J M , HUANG S B , WU T T , et al. Prognostic impact of Beclin 1, p62/sequestosome 1 and LC3 protein expression in colon carcinomas from patients receiving 5-fluorouracil as adjuvant chemotherapy [J ] . Cancer Biol Ther , 2013 , 14 ( 2 ): 100 - 107 . DOI: 10.4161/cbt.22954 http://doi.org/10.4161/cbt.22954 http://www.tandfonline.com/doi/abs/10.4161/cbt.22954 http://www.tandfonline.com/doi/abs/10.4161/cbt.22954

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