ISSN 0253-2778

CN 34-1054/N

Open AccessOpen Access JUSTC Life Sciences and Medicine

Diagnostic role of NPY methylation in patients with colorectal cancer

Cite this:
https://doi.org/10.52396/JUSTC-2022-0027
More Information
  • Author Bio:

    Jing Wang received her Ph.D. degree in Oncology from the Sun Yat-sen University Cancer Center in 2018. Her research focuses mainly on tumor detection and pathology

    Yuan He received her Ph.D. degree in Oncology from the Sun Yat-sen University Cancer Center in 2019. She was an assistant researcher in the Sun Yat-sen University Cancer Center from 2019 to 2021. She is currently a doctor in the First Affiliated Hospital of University of Science and Technology of China. Her research interests include cancer biology, epigenetic, tumor radiosensitivity, and artificial intelligence

  • Corresponding author: E-mail: heyuan3766@126.com
  • Received Date: 05 February 2022
  • Accepted Date: 23 March 2022
  • Objectives: A growing number of studies have shown that methylation biomarkers play an important role in oncogenesis. This study aimed to explore the diagnostic role of neuropeptide Y (NPY) methylation in colorectal cancer (CRC).Methods: mRNA and protein expression, methylation, survival benefits, and immune cell infiltration were analyzed using bioinformatics tools across all tumors from The Cancer Genome Atlas. NPY methylation in CRC was further validated in CRC tissues, fecal samples, and cell lines. Analyses of NPY methylation were performed using Sequenome EpiTYPER and quantitative PCR. Retrieval of NPY expression in cell lines was tested using real-time PCR and western blotting.Results: Bioinformatic analysis showed that the methylation level of NPY increased in most carcinomas (P<0.05). Moreover, statistical correlations were observed between NPY transcriptional expression and CD4+ T cells, macrophages, and dendritic cells in colon cancer (P<0.05). Similar results were obtained for CD4+ T cells, neutrophils, and NPY in rectal cancer (P<0.05). Our results showed that NPY was hypermethylated in CRC tissues and fecal exfoliated cells (P<0.05). Fecal NPY methylation was observed in 82.5% sensitive for primary tumors, 46.3% for intestinal polyps (including adenomatous, serrated, and inflammatory polyps), and 23.4% of healthy controls. Overall, fecal NPY methylation was 76.6% specific. For cell lines, in vivo experiments demonstrated that 5-aza-2′-deoxycytidine downregulated the methylation of NPY and restored its mRNA level (P<0.05).Conclusions: This study indicates that NPY is hypermethylated in CRC, and that NPY methylation in fecal DNA is a potential noninvasive diagnostic biomarker for Chinese patients with CRC.
    Diagnostic role of neuropeptide Y (NPY) methylation in colorectal cancer (CRC).
    Objectives: A growing number of studies have shown that methylation biomarkers play an important role in oncogenesis. This study aimed to explore the diagnostic role of neuropeptide Y (NPY) methylation in colorectal cancer (CRC).Methods: mRNA and protein expression, methylation, survival benefits, and immune cell infiltration were analyzed using bioinformatics tools across all tumors from The Cancer Genome Atlas. NPY methylation in CRC was further validated in CRC tissues, fecal samples, and cell lines. Analyses of NPY methylation were performed using Sequenome EpiTYPER and quantitative PCR. Retrieval of NPY expression in cell lines was tested using real-time PCR and western blotting.Results: Bioinformatic analysis showed that the methylation level of NPY increased in most carcinomas (P<0.05). Moreover, statistical correlations were observed between NPY transcriptional expression and CD4+ T cells, macrophages, and dendritic cells in colon cancer (P<0.05). Similar results were obtained for CD4+ T cells, neutrophils, and NPY in rectal cancer (P<0.05). Our results showed that NPY was hypermethylated in CRC tissues and fecal exfoliated cells (P<0.05). Fecal NPY methylation was observed in 82.5% sensitive for primary tumors, 46.3% for intestinal polyps (including adenomatous, serrated, and inflammatory polyps), and 23.4% of healthy controls. Overall, fecal NPY methylation was 76.6% specific. For cell lines, in vivo experiments demonstrated that 5-aza-2′-deoxycytidine downregulated the methylation of NPY and restored its mRNA level (P<0.05).Conclusions: This study indicates that NPY is hypermethylated in CRC, and that NPY methylation in fecal DNA is a potential noninvasive diagnostic biomarker for Chinese patients with CRC.
    • The methylation level of europeptide Y (NPY) was increased in most carcinomas, including colorectal cancer (CRC).
    • Fecal NPY methylation appears to be associated with good diagnostic ability in patients with CRC.
    • In vivo experiments demonstrated that 5-AZC downregulated NPY methylation and restored its mRNA level.

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    [3]
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    [4]
    Nakade S, Yamamoto T, Sakuma T. Cancer induction and suppression with transcriptional control and epigenome editing technologies. J. Hum. Genet., 2018, 63 (2): 187–194. doi: 10.1038/s10038-017-0377-8
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    [8]
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    [10]
    Domschke K, Dannlowski U, Hohoff C, et al. Neuropeptide Y (NPY) gene: Impact on emotional processing and treatment response in anxious depression. Eur. Neuropsychopharmacol., 2010, 20 (5): 301–309. doi: 10.1016/j.euroneuro.2009.09.006
    [11]
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    [12]
    Rasiah K K, Kench J G, Gardiner-Garden M, et al. Aberrant neuropeptide Y and macrophage inhibitory cytokine-1 expression are early events in prostate cancer development and are associated with poor prognosis. Cancer Epidemiol. Biomarkers Prev., 2006, 15 (4): 711–716. doi: 10.1158/1055-9965.EPI-05-0752
    [13]
    Zhang J, Dhakal I B, Zhang X, et al. Genetic variability in energy balance and pancreatic cancer risk in a population-based case-control study in Minnesota. Pancreas, 2014, 43 (2): 281–286. doi: 10.1097/MPA.0b013e3182a7c829
    [14]
    Zhang Y Z, Fang L, Zang Y W, et al. Identifcation of core genes and key pathways via integrated analysis of gene expression and DNA methylation profles in bladder cancer. Med. Sci. Monit., 2018, 24: 3024–3033. doi: 10.12659/MSM.909514
    [15]
    Wentzensen N, Bakkum-Gamez J N, Killian J K, et al. Discovery and validation of methylation markers for endometrial cancer. Int. J. Cancer, 2014, 135 (8): 1860–1868. doi: 10.1002/ijc.28843
    [16]
    Chang W L, Lai W W, Kuo I Y, et al. A six-CpG panel with DNA methylation biomarkers predicting treatment response of chemoradiation in esophageal squamous cell carcinoma. J. Gastroenterol., 2017, 52 (6): 705–714. doi: 10.1007/s00535-016-1265-2
    [17]
    Misawa K, Mima M, Imai A, et al. The neuropeptide genes SST, TAC1, HCRT, NPY, and GAL are powerful epigenetic biomarkers in head and neck cancer: a site-specific analysis. Clin. Epigenetics, 2018, 10: 52. doi: 10.1186/s13148-018-0485-0
    [18]
    Tilan J, Kitlinska J. Neuropeptide Y (NPY) in tumor growth and progression: lessons learned from pediatric oncology. Neuropeptides, 2016, 55: 55–66. doi: 10.1016/j.npep.2015.10.005
    [19]
    Roperch J P, Benzekri K, Mansour H, et al. Improved amplification efficiency on stool samples by addition of spermidine and its use for non-invasive detection of colorectal cancer. BMC Biotechnol., 2015, 15: 41. doi: 10.1186/s12896-015-0148-6
    [20]
    Kim Y H, Lee H C, Kim S Y, et al. Epigenomic analysis of aberrantly methylated genes in colorectal cancer identifies genes commonly affected by epigenetic alterations. Ann. Surg. Oncol., 2011, 18 (8): 2338–2347. doi: 10.1245/s10434-011-1573-y
    [21]
    Roperch J P, Incitti R, Forbin S, et al. Aberrant methylation of NPY, PENK, and WIF1 as a promising marker for blood-based diagnosis of colorectal cancer. BMC Cancer, 2013, 13: 566. doi: 10.1186/1471-2407-13-566
    [22]
    Garrigou S, Perkins G, Garlan F, et al. A study of hypermethylated circulating tumor DNA as a universal colorectal cancer biomarker. Clin. Chem., 2016, 62 (8): 1129–1139. doi: 10.1373/clinchem.2015.253609
    [23]
    Kitlinska J, Abe K, Kuo L, et al. Differential effects of neuropeptide Y on the growth and vascularization of neural crest-derived tumors. Cancer Res., 2005, 65 (5): 1719–1728. doi: 10.1158/0008-5472.CAN-04-2192
    [24]
    Lu C, Everhart L, Tilan J, et al. Neuropeptide Y and its Y2 receptor: potential targets in neuroblastoma therapy. Oncogene, 2010, 29 (41): 5630–5642. doi: 10.1038/onc.2010.301
    [25]
    Czarnecka M, Trinh E, Lu C, et al. Neuropeptide Y receptor Y5 as an inducible pro-survival factor in neuroblastoma: implications for tumor chemoresistance. Oncogene, 2015, 34 (24): 3131–3143. doi: 10.1038/onc.2014.253
    [26]
    Tilan J U, Krailo M, Barkauskas D A, et al. Systemic levels of neuropeptide Y and dipeptidyl peptidase activity in Ewing sarcoma patients-associations with tumor phenotype and survival. Cancer, 2015, 121 (5): 697–707. doi: 10.1002/cncr.29090
    [27]
    Ruscica M, Dozio E, Boghossian S, et al. Activation of the Y1 receptor by neuropeptide Y regulates the growth of prostate cancer cells. Endocrinology, 2006, 147 (3): 1466–1473. doi: 10.1210/en.2005-0925
    [28]
    Medeiros P J, Al-Khazraji B K, Novielli N M, et al. Neuropeptide Y stimulates proliferation and migration in the 4T1 breast cancer cell line. Int. J. Cancer, 2012, 131 (2): 276–286. doi: 10.1002/ijc.26350
    [29]
    Li Y F, Hsiao Y H, Lai Y H, et al. DNA methylation profiles and biomarkers of oral squamous cell carcinoma. Epigenetics, 2015, 10 (3): 229–236. doi: 10.1080/15592294.2015.1006506
    [30]
    Diaz-delCastillo M, Christiansen S H, Appel C K, et al. Neuropeptide Y is up-regulated and induces antinociception in cancer-induced bone pain. Neuroscience, 2018, 384: 111–119. doi: 10.1016/j.neuroscience.2018.05.025
    [31]
    Renehan A G. Bariatric surgery, weight reduction, and cancer prevention. Lancet Oncol., 2009, 10 (7): 640–641. doi: 10.1016/S1470-2045(09)70170-6
    [32]
    Meguid M M, Ramos E J, Laviano A, et al. Tumor anorexia: effects on neuropeptide Y and monoamines in paraventricular nucleus. Peptides, 2004, 25 (2): 261–266. doi: 10.1016/j.peptides.2004.01.012
    [33]
    Zhang L, Bijker M S, Herzog H. The neuropeptide Y system: Pathophysiological and therapeutic implications in obesity and cancer. Pharmacol. Ther., 2011, 131 (1): 91–113. doi: 10.1016/j.pharmthera.2011.03.011
    [34]
    Mendoza-Pérez J, Gu J, Herrera L A, et al. Prognostic significance of promoter CpG island methylation of obesity-related genes in patients with nonmetastatic renal cell carcinoma. Cancer, 2017, 123 (18): 3617–3627. doi: 10.1002/cncr.30707
    [35]
    Farzi A, Reichmann F, Holzer P. The homeostatic role of neuropeptide Y in immune function and its impact on mood and behaviour. Acta Physiol (Oxf. ), 2015, 213 (3): 603–627. doi: 10.1111/apha.12445
    [36]
    Garlan F, Laurent-Puig P, Sefrioui D, et al. Early evaluation of circulating tumor DNA as marker of therapeutic efficacy in metastatic colorectal cancer patients (PLACOL study). Clin. Cancer Res., 2017, 23 (18): 5416–5425. doi: 10.1158/1078-0432.CCR-16-3155
    [37]
    Boeckx N, Op de Beeck K, Beyens M, et al. Mutation and methylation analysis of circulating tumor DNA can be used for follow-up of metastatic colorectal cancer patients. Clin. Colorectal Cancer, 2018, 17 (2): e369–e379. doi: 10.1016/j.clcc.2018.02.006
    [38]
    Ogasawara M, Murata J, Ayukawa K, et al. Differential effect of intestinal neuropeptides on invasion and migration of colon carcinoma cells in vitro. Cancer Lett., 1997, 119 (1): 125–130. doi: 10.1016/S0304-3835(97)81762-4
  • 加载中

Catalog

    Figure  1.  (a) The expression status of NPY gene in different cancer cell lines through the database of Cancer Cell Line Encyclopedia. (b) The NPY expression was explored in tumor tissues from GEPIA (**P<0.01, ***P<0.001). (c) Based on the CPTAC dataset, the expression level of NPY total protein was analyzed between normal tissue and primary tissue of LUAD, BRCA, OV, KIRC, and UCEC (*P<0.05). (d) Based on the TCGA data, the expression level of NPY was analyzed by the pathological stages (stage I, stage II, stage III, and stage IV) of COAD, TGCT, and UCEC (P<0.05). (e) Correlation between NPY and overall survival / disease-free survival prognosis of cancers in TCGA.

    Figure  2.  Methylation feature of NPY in different tumors of TCGA (*P<0.05).

    Figure  3.  Representive correlation analysis between NPY and immune infiltration cells.

    Figure  4.  Sequenom EpiTYPER system analysis of the average methylation ratio of NPY in CRC tissues. (a) The methylation level of NPY was significantly up-regulated in colorectal cancer compared to normal tissues (P<0.05). (b) All subgroup target CpG sites showed the same statistical differences (*P<0.0001). (c) ROC analysis of NPY methylation in CRC tissues: the AUC, sensitivity and specificity of NPY methylation were 0.83, 78.5%, 87.5%, respectively. (d) Kaplan-Meier survival analysis of NPY methylation for overall survival in colorectal cancer (P=0.32).

    Figure  5.  ROC curve analysis of NPY methylation in fecal samples. (a) The sensitivity, specificity, and AUC value of fecal NPY methylation test for the diagnosis of colorectal cancer were 82.5%, 76.6%, and 0.79, respectively. (b) The sensitivity, specificity, and AUC value of fecal NPY methylation test and fecal immunochemical test for the diagnosis of colorectal cancer were 98.3%, 76.6%, and 0.87, respectively.

    Figure  6.  (a, c) Sequenom EpiTYPER system analysis of the average methylation ratio of NPY in CRC cell lines treated with 5-Aza-2’-deoxycytidine (0 μmol/L vs 5 μmol/L vs 10 μmol/L) (*P<0.05). (b) SYBR analysis of the relative mRNA level of NPY in CRC cell lines treated with 5-Aza-2’-deoxycytidine (0 μmol/L vs 5 μmol/L vs 10 μmol/L) (*P<0.05). (d) Western blot analysis of the protein level of NPY in CRC cell lines treated with 5-Aza-2’-deoxycytidine (0 μmol/L vs 5 μmol/L vs 10 μmol/L) (P<0.05).

    [1]
    Chen W Q, Zheng R S, Baade P D, et al. Cancer statistics in China, 2015. CA Cancer J. Clin., 2016, 66 (2): 115–132. doi: 10.3322/caac.21338
    [2]
    Amelio I, Bertolo R, Bove P, et al. Liquid biopsies and cancer omics. Cell Death Discov., 2020, 6 (1): 131. doi: 10.1038/s41420-020-00373-0
    [3]
    Delpu Y, Cordelier P, Cho W C, et al. DNA methylation and cancer diagnosis. Int. J. Mol. Sci., 2013, 14 (7): 15029–15058. doi: 10.3390/ijms140715029
    [4]
    Nakade S, Yamamoto T, Sakuma T. Cancer induction and suppression with transcriptional control and epigenome editing technologies. J. Hum. Genet., 2018, 63 (2): 187–194. doi: 10.1038/s10038-017-0377-8
    [5]
    Hu C H, Liu X H, Zeng Y, et al. DNA methyltransferase inhibitors combination therapy for the treatment of solid tumor: mechanism and clinical application. Clin. Epigenetics, 2021, 13 (1): 166. doi: 10.1186/s13148-021-01154-x
    [6]
    El-Salhy M, Hausken T. The role of the neuropeptide Y (NPY) family in the pathophysiology of inflammatory bowel disease (IBD). Neuropeptides, 2016, 55: 137–144. doi: 10.1016/j.npep.2015.09.005
    [7]
    Li Z B, Heng J F, Yan J H, et al. Integrated analysis of gene expression and methylation profiles of 48 candidate genes in breast cancer patients. Breast Cancer Res. Treat., 2016, 160 (2): 371–383. doi: 10.1007/s10549-016-4004-8
    [8]
    Belai A, Boulos P B, Robson T, et al. Neurochemical coding in the small intestine of patients with Crohn's disease. Gut, 1997, 40 (6): 767–774. doi: 10.1136/gut.40.6.767
    [9]
    Tan C M J, Green P, Tapoulal N, et al. The Role of neuropeptide Y in cardiovascular health and disease. Front. Physiol., 2018, 9: 1281. doi: 10.3389/fphys.2018.01281
    [10]
    Domschke K, Dannlowski U, Hohoff C, et al. Neuropeptide Y (NPY) gene: Impact on emotional processing and treatment response in anxious depression. Eur. Neuropsychopharmacol., 2010, 20 (5): 301–309. doi: 10.1016/j.euroneuro.2009.09.006
    [11]
    Shin S H, Kim B H, Jang J J, et al. Identifcation of novel methylation markers in hepatocellular carcinoma using a methylation array. J. Korean Med. Sci., 2010, 25 (8): 1152–1159. doi: 10.3346/jkms.2010.25.8.1152
    [12]
    Rasiah K K, Kench J G, Gardiner-Garden M, et al. Aberrant neuropeptide Y and macrophage inhibitory cytokine-1 expression are early events in prostate cancer development and are associated with poor prognosis. Cancer Epidemiol. Biomarkers Prev., 2006, 15 (4): 711–716. doi: 10.1158/1055-9965.EPI-05-0752
    [13]
    Zhang J, Dhakal I B, Zhang X, et al. Genetic variability in energy balance and pancreatic cancer risk in a population-based case-control study in Minnesota. Pancreas, 2014, 43 (2): 281–286. doi: 10.1097/MPA.0b013e3182a7c829
    [14]
    Zhang Y Z, Fang L, Zang Y W, et al. Identifcation of core genes and key pathways via integrated analysis of gene expression and DNA methylation profles in bladder cancer. Med. Sci. Monit., 2018, 24: 3024–3033. doi: 10.12659/MSM.909514
    [15]
    Wentzensen N, Bakkum-Gamez J N, Killian J K, et al. Discovery and validation of methylation markers for endometrial cancer. Int. J. Cancer, 2014, 135 (8): 1860–1868. doi: 10.1002/ijc.28843
    [16]
    Chang W L, Lai W W, Kuo I Y, et al. A six-CpG panel with DNA methylation biomarkers predicting treatment response of chemoradiation in esophageal squamous cell carcinoma. J. Gastroenterol., 2017, 52 (6): 705–714. doi: 10.1007/s00535-016-1265-2
    [17]
    Misawa K, Mima M, Imai A, et al. The neuropeptide genes SST, TAC1, HCRT, NPY, and GAL are powerful epigenetic biomarkers in head and neck cancer: a site-specific analysis. Clin. Epigenetics, 2018, 10: 52. doi: 10.1186/s13148-018-0485-0
    [18]
    Tilan J, Kitlinska J. Neuropeptide Y (NPY) in tumor growth and progression: lessons learned from pediatric oncology. Neuropeptides, 2016, 55: 55–66. doi: 10.1016/j.npep.2015.10.005
    [19]
    Roperch J P, Benzekri K, Mansour H, et al. Improved amplification efficiency on stool samples by addition of spermidine and its use for non-invasive detection of colorectal cancer. BMC Biotechnol., 2015, 15: 41. doi: 10.1186/s12896-015-0148-6
    [20]
    Kim Y H, Lee H C, Kim S Y, et al. Epigenomic analysis of aberrantly methylated genes in colorectal cancer identifies genes commonly affected by epigenetic alterations. Ann. Surg. Oncol., 2011, 18 (8): 2338–2347. doi: 10.1245/s10434-011-1573-y
    [21]
    Roperch J P, Incitti R, Forbin S, et al. Aberrant methylation of NPY, PENK, and WIF1 as a promising marker for blood-based diagnosis of colorectal cancer. BMC Cancer, 2013, 13: 566. doi: 10.1186/1471-2407-13-566
    [22]
    Garrigou S, Perkins G, Garlan F, et al. A study of hypermethylated circulating tumor DNA as a universal colorectal cancer biomarker. Clin. Chem., 2016, 62 (8): 1129–1139. doi: 10.1373/clinchem.2015.253609
    [23]
    Kitlinska J, Abe K, Kuo L, et al. Differential effects of neuropeptide Y on the growth and vascularization of neural crest-derived tumors. Cancer Res., 2005, 65 (5): 1719–1728. doi: 10.1158/0008-5472.CAN-04-2192
    [24]
    Lu C, Everhart L, Tilan J, et al. Neuropeptide Y and its Y2 receptor: potential targets in neuroblastoma therapy. Oncogene, 2010, 29 (41): 5630–5642. doi: 10.1038/onc.2010.301
    [25]
    Czarnecka M, Trinh E, Lu C, et al. Neuropeptide Y receptor Y5 as an inducible pro-survival factor in neuroblastoma: implications for tumor chemoresistance. Oncogene, 2015, 34 (24): 3131–3143. doi: 10.1038/onc.2014.253
    [26]
    Tilan J U, Krailo M, Barkauskas D A, et al. Systemic levels of neuropeptide Y and dipeptidyl peptidase activity in Ewing sarcoma patients-associations with tumor phenotype and survival. Cancer, 2015, 121 (5): 697–707. doi: 10.1002/cncr.29090
    [27]
    Ruscica M, Dozio E, Boghossian S, et al. Activation of the Y1 receptor by neuropeptide Y regulates the growth of prostate cancer cells. Endocrinology, 2006, 147 (3): 1466–1473. doi: 10.1210/en.2005-0925
    [28]
    Medeiros P J, Al-Khazraji B K, Novielli N M, et al. Neuropeptide Y stimulates proliferation and migration in the 4T1 breast cancer cell line. Int. J. Cancer, 2012, 131 (2): 276–286. doi: 10.1002/ijc.26350
    [29]
    Li Y F, Hsiao Y H, Lai Y H, et al. DNA methylation profiles and biomarkers of oral squamous cell carcinoma. Epigenetics, 2015, 10 (3): 229–236. doi: 10.1080/15592294.2015.1006506
    [30]
    Diaz-delCastillo M, Christiansen S H, Appel C K, et al. Neuropeptide Y is up-regulated and induces antinociception in cancer-induced bone pain. Neuroscience, 2018, 384: 111–119. doi: 10.1016/j.neuroscience.2018.05.025
    [31]
    Renehan A G. Bariatric surgery, weight reduction, and cancer prevention. Lancet Oncol., 2009, 10 (7): 640–641. doi: 10.1016/S1470-2045(09)70170-6
    [32]
    Meguid M M, Ramos E J, Laviano A, et al. Tumor anorexia: effects on neuropeptide Y and monoamines in paraventricular nucleus. Peptides, 2004, 25 (2): 261–266. doi: 10.1016/j.peptides.2004.01.012
    [33]
    Zhang L, Bijker M S, Herzog H. The neuropeptide Y system: Pathophysiological and therapeutic implications in obesity and cancer. Pharmacol. Ther., 2011, 131 (1): 91–113. doi: 10.1016/j.pharmthera.2011.03.011
    [34]
    Mendoza-Pérez J, Gu J, Herrera L A, et al. Prognostic significance of promoter CpG island methylation of obesity-related genes in patients with nonmetastatic renal cell carcinoma. Cancer, 2017, 123 (18): 3617–3627. doi: 10.1002/cncr.30707
    [35]
    Farzi A, Reichmann F, Holzer P. The homeostatic role of neuropeptide Y in immune function and its impact on mood and behaviour. Acta Physiol (Oxf. ), 2015, 213 (3): 603–627. doi: 10.1111/apha.12445
    [36]
    Garlan F, Laurent-Puig P, Sefrioui D, et al. Early evaluation of circulating tumor DNA as marker of therapeutic efficacy in metastatic colorectal cancer patients (PLACOL study). Clin. Cancer Res., 2017, 23 (18): 5416–5425. doi: 10.1158/1078-0432.CCR-16-3155
    [37]
    Boeckx N, Op de Beeck K, Beyens M, et al. Mutation and methylation analysis of circulating tumor DNA can be used for follow-up of metastatic colorectal cancer patients. Clin. Colorectal Cancer, 2018, 17 (2): e369–e379. doi: 10.1016/j.clcc.2018.02.006
    [38]
    Ogasawara M, Murata J, Ayukawa K, et al. Differential effect of intestinal neuropeptides on invasion and migration of colon carcinoma cells in vitro. Cancer Lett., 1997, 119 (1): 125–130. doi: 10.1016/S0304-3835(97)81762-4

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