<I>DKK1</I> Promoter Methylation in Colorectal Cancer Is Associated with CIMP and Elevation of <I>MYC</I> Expression

Mie Yoshimura; Kazuo Tamura; Tomoki Yamano; Nagahide Matsubara; Akihito Babaya; Michiko Yasuhara; Aya Yano; Miki Fukumoto; Norihito Kawashita; Junko Tatsumi-Miyajima; Naohiro Tomita

doi:doi:10.11648/j.ijg.20220601.13

DKK1 Promoter Methylation in Colorectal Cancer Is Associated with CIMP and Elevation of MYC Expression

Mie Yoshimura, Kazuo Tamura, Tomoki Yamano, Nagahide Matsubara, Akihito Babaya, Michiko Yasuhara, Aya Yano, Miki Fukumoto, Norihito Kawashita, Junko Tatsumi-Miyajima, Naohiro Tomita

Published in International Journal of Gastroenterology (Volume 6, Issue 1)

Received: 11 April 2022 Accepted: 3 May 2022 Published: 12 May 2022

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Abstract

Background: Carcinogenesis of colorectal cancer (CRC) is influenced greatly by the canonical WNT signaling pathway. Genetically, the secreted protein Dickkopf (Dkk) family is known as an antagonist to the WNT. To clarify the role of DKK1 in the WNT signaling pathway in the colorectal carcinogenesis, we examined the DKK1 promoter methylation in CRC and analyze the relationship of expression level of DKK1 and MYC in relation with APC gene abnormalities. Methods: We integrated clinico-pathological and molecular findings of 41 cases of CRC. We adopted methylation-specific PCR, DNA sequencing, allelic loss analysis, quantitative RT-PCR, and MSI testing for genetic analyses. Results: CRCs with DKK1 promotor methylation were found in 10 cases (24.4%), which were located predominantly in the proximal colon and frequently showed findings of poorly differentiated adenocarcinoma or mucinous adenocarcinoma. Furthermore, colorectal cancers with DKK1 promotor methylation showed characteristics of microsatellite instability (MSI)-high (70%) and a BRAF mutation (40%), which are known as the CpG island methylator phenotype (CIMP). In the DKK1 promotor methylation group, the relative expression level of DKK1 mRNA was significantly reduced in comparison to the DKK1 promotor un-methylation group (p < 0.05). When excluding the impact of APC abnormality, MYC expression in the DKK1 promotor methylation group was significantly elevated compared to that in the DKK1 promotor un-methylation group (p < 0.05). Conclusions: It is suggested that DKK1 is one of the regulators involved in MYC expression through the WNT signaling pathway and may have a negative effect on carcinogenesis of the colorectum without APC abnormalities.

Published in	International Journal of Gastroenterology (Volume 6, Issue 1)
DOI	10.11648/j.ijg.20220601.13
Page(s)	9-17
Creative Commons	This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.
Copyright	Copyright © The Author(s), 2022. Published by Science Publishing Group

Keywords

DKK1, MYC, WNT Signaling Pathway, Methylation, Colorectal Cancer, CIMP

References

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APA Style

Mie Yoshimura, Kazuo Tamura, Tomoki Yamano, Nagahide Matsubara, Akihito Babaya, et al. (2022). DKK1 Promoter Methylation in Colorectal Cancer Is Associated with CIMP and Elevation of MYC Expression. International Journal of Gastroenterology, 6(1), 9-17. https://doi.org/10.11648/j.ijg.20220601.13

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ACS Style

Mie Yoshimura; Kazuo Tamura; Tomoki Yamano; Nagahide Matsubara; Akihito Babaya, et al. DKK1 Promoter Methylation in Colorectal Cancer Is Associated with CIMP and Elevation of MYC Expression. Int. J. Gastroenterol. 2022, 6(1), 9-17. doi: 10.11648/j.ijg.20220601.13

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AMA Style

Mie Yoshimura, Kazuo Tamura, Tomoki Yamano, Nagahide Matsubara, Akihito Babaya, et al. DKK1 Promoter Methylation in Colorectal Cancer Is Associated with CIMP and Elevation of MYC Expression. Int J Gastroenterol. 2022;6(1):9-17. doi: 10.11648/j.ijg.20220601.13

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@article{10.11648/j.ijg.20220601.13,
  author = {Mie Yoshimura and Kazuo Tamura and Tomoki Yamano and Nagahide Matsubara and Akihito Babaya and Michiko Yasuhara and Aya Yano and Miki Fukumoto and Norihito Kawashita and Junko Tatsumi-Miyajima and Naohiro Tomita},
  title = {DKK1 Promoter Methylation in Colorectal Cancer Is Associated with CIMP and Elevation of MYC Expression},
  journal = {International Journal of Gastroenterology},
  volume = {6},
  number = {1},
  pages = {9-17},
  doi = {10.11648/j.ijg.20220601.13},
  url = {https://doi.org/10.11648/j.ijg.20220601.13},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ijg.20220601.13},
  abstract = {Background: Carcinogenesis of colorectal cancer (CRC) is influenced greatly by the canonical WNT signaling pathway. Genetically, the secreted protein Dickkopf (Dkk) family is known as an antagonist to the WNT. To clarify the role of DKK1 in the WNT signaling pathway in the colorectal carcinogenesis, we examined the DKK1 promoter methylation in CRC and analyze the relationship of expression level of DKK1 and MYC in relation with APC gene abnormalities. Methods: We integrated clinico-pathological and molecular findings of 41 cases of CRC. We adopted methylation-specific PCR, DNA sequencing, allelic loss analysis, quantitative RT-PCR, and MSI testing for genetic analyses. Results: CRCs with DKK1 promotor methylation were found in 10 cases (24.4%), which were located predominantly in the proximal colon and frequently showed findings of poorly differentiated adenocarcinoma or mucinous adenocarcinoma. Furthermore, colorectal cancers with DKK1 promotor methylation showed characteristics of microsatellite instability (MSI)-high (70%) and a BRAF mutation (40%), which are known as the CpG island methylator phenotype (CIMP). In the DKK1 promotor methylation group, the relative expression level of DKK1 mRNA was significantly reduced in comparison to the DKK1 promotor un-methylation group (p MYC expression in the DKK1 promotor methylation group was significantly elevated compared to that in the DKK1 promotor un-methylation group (p Conclusions: It is suggested that DKK1 is one of the regulators involved in MYC expression through the WNT signaling pathway and may have a negative effect on carcinogenesis of the colorectum without APC abnormalities.},
 year = {2022}
}

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TY  - JOUR
T1  - DKK1 Promoter Methylation in Colorectal Cancer Is Associated with CIMP and Elevation of MYC Expression
AU  - Mie Yoshimura
AU  - Kazuo Tamura
AU  - Tomoki Yamano
AU  - Nagahide Matsubara
AU  - Akihito Babaya
AU  - Michiko Yasuhara
AU  - Aya Yano
AU  - Miki Fukumoto
AU  - Norihito Kawashita
AU  - Junko Tatsumi-Miyajima
AU  - Naohiro Tomita
Y1  - 2022/05/12
PY  - 2022
N1  - https://doi.org/10.11648/j.ijg.20220601.13
DO  - 10.11648/j.ijg.20220601.13
T2  - International Journal of Gastroenterology
JF  - International Journal of Gastroenterology
JO  - International Journal of Gastroenterology
SP  - 9
EP  - 17
PB  - Science Publishing Group
SN  - 2640-169X
UR  - https://doi.org/10.11648/j.ijg.20220601.13
AB  - Background: Carcinogenesis of colorectal cancer (CRC) is influenced greatly by the canonical WNT signaling pathway. Genetically, the secreted protein Dickkopf (Dkk) family is known as an antagonist to the WNT. To clarify the role of DKK1 in the WNT signaling pathway in the colorectal carcinogenesis, we examined the DKK1 promoter methylation in CRC and analyze the relationship of expression level of DKK1 and MYC in relation with APC gene abnormalities. Methods: We integrated clinico-pathological and molecular findings of 41 cases of CRC. We adopted methylation-specific PCR, DNA sequencing, allelic loss analysis, quantitative RT-PCR, and MSI testing for genetic analyses. Results: CRCs with DKK1 promotor methylation were found in 10 cases (24.4%), which were located predominantly in the proximal colon and frequently showed findings of poorly differentiated adenocarcinoma or mucinous adenocarcinoma. Furthermore, colorectal cancers with DKK1 promotor methylation showed characteristics of microsatellite instability (MSI)-high (70%) and a BRAF mutation (40%), which are known as the CpG island methylator phenotype (CIMP). In the DKK1 promotor methylation group, the relative expression level of DKK1 mRNA was significantly reduced in comparison to the DKK1 promotor un-methylation group (p MYC expression in the DKK1 promotor methylation group was significantly elevated compared to that in the DKK1 promotor un-methylation group (p Conclusions: It is suggested that DKK1 is one of the regulators involved in MYC expression through the WNT signaling pathway and may have a negative effect on carcinogenesis of the colorectum without APC abnormalities.
VL  - 6
IS  - 1
ER  -

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Author Information

Mie Yoshimura

Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
Kazuo Tamura

Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
Tomoki Yamano

Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
Nagahide Matsubara

Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
Akihito Babaya

Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
Michiko Yasuhara

Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
Aya Yano

Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
Miki Fukumoto

Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
Norihito Kawashita

Division of Genetic Medicine, Master of Science, Graduate School of Science and Engineering Research, Kindai University, Higashiosaka, Japan
Junko Tatsumi-Miyajima

Division of Genetic Medicine, Master of Science, Graduate School of Science and Engineering Research, Kindai University, Higashiosaka, Japan
Naohiro Tomita

Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan

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APA Style

Mie Yoshimura, Kazuo Tamura, Tomoki Yamano, Nagahide Matsubara, Akihito Babaya, et al. (2022). DKK1 Promoter Methylation in Colorectal Cancer Is Associated with CIMP and Elevation of MYC Expression. International Journal of Gastroenterology, 6(1), 9-17. https://doi.org/10.11648/j.ijg.20220601.13

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ACS Style

Mie Yoshimura; Kazuo Tamura; Tomoki Yamano; Nagahide Matsubara; Akihito Babaya, et al. DKK1 Promoter Methylation in Colorectal Cancer Is Associated with CIMP and Elevation of MYC Expression. Int. J. Gastroenterol. 2022, 6(1), 9-17. doi: 10.11648/j.ijg.20220601.13

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AMA Style

Mie Yoshimura, Kazuo Tamura, Tomoki Yamano, Nagahide Matsubara, Akihito Babaya, et al. DKK1 Promoter Methylation in Colorectal Cancer Is Associated with CIMP and Elevation of MYC Expression. Int J Gastroenterol. 2022;6(1):9-17. doi: 10.11648/j.ijg.20220601.13

Copy | Download

@article{10.11648/j.ijg.20220601.13,
  author = {Mie Yoshimura and Kazuo Tamura and Tomoki Yamano and Nagahide Matsubara and Akihito Babaya and Michiko Yasuhara and Aya Yano and Miki Fukumoto and Norihito Kawashita and Junko Tatsumi-Miyajima and Naohiro Tomita},
  title = {DKK1 Promoter Methylation in Colorectal Cancer Is Associated with CIMP and Elevation of MYC Expression},
  journal = {International Journal of Gastroenterology},
  volume = {6},
  number = {1},
  pages = {9-17},
  doi = {10.11648/j.ijg.20220601.13},
  url = {https://doi.org/10.11648/j.ijg.20220601.13},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ijg.20220601.13},
  abstract = {Background: Carcinogenesis of colorectal cancer (CRC) is influenced greatly by the canonical WNT signaling pathway. Genetically, the secreted protein Dickkopf (Dkk) family is known as an antagonist to the WNT. To clarify the role of DKK1 in the WNT signaling pathway in the colorectal carcinogenesis, we examined the DKK1 promoter methylation in CRC and analyze the relationship of expression level of DKK1 and MYC in relation with APC gene abnormalities. Methods: We integrated clinico-pathological and molecular findings of 41 cases of CRC. We adopted methylation-specific PCR, DNA sequencing, allelic loss analysis, quantitative RT-PCR, and MSI testing for genetic analyses. Results: CRCs with DKK1 promotor methylation were found in 10 cases (24.4%), which were located predominantly in the proximal colon and frequently showed findings of poorly differentiated adenocarcinoma or mucinous adenocarcinoma. Furthermore, colorectal cancers with DKK1 promotor methylation showed characteristics of microsatellite instability (MSI)-high (70%) and a BRAF mutation (40%), which are known as the CpG island methylator phenotype (CIMP). In the DKK1 promotor methylation group, the relative expression level of DKK1 mRNA was significantly reduced in comparison to the DKK1 promotor un-methylation group (p MYC expression in the DKK1 promotor methylation group was significantly elevated compared to that in the DKK1 promotor un-methylation group (p Conclusions: It is suggested that DKK1 is one of the regulators involved in MYC expression through the WNT signaling pathway and may have a negative effect on carcinogenesis of the colorectum without APC abnormalities.},
 year = {2022}
}

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TY  - JOUR
T1  - DKK1 Promoter Methylation in Colorectal Cancer Is Associated with CIMP and Elevation of MYC Expression
AU  - Mie Yoshimura
AU  - Kazuo Tamura
AU  - Tomoki Yamano
AU  - Nagahide Matsubara
AU  - Akihito Babaya
AU  - Michiko Yasuhara
AU  - Aya Yano
AU  - Miki Fukumoto
AU  - Norihito Kawashita
AU  - Junko Tatsumi-Miyajima
AU  - Naohiro Tomita
Y1  - 2022/05/12
PY  - 2022
N1  - https://doi.org/10.11648/j.ijg.20220601.13
DO  - 10.11648/j.ijg.20220601.13
T2  - International Journal of Gastroenterology
JF  - International Journal of Gastroenterology
JO  - International Journal of Gastroenterology
SP  - 9
EP  - 17
PB  - Science Publishing Group
SN  - 2640-169X
UR  - https://doi.org/10.11648/j.ijg.20220601.13
AB  - Background: Carcinogenesis of colorectal cancer (CRC) is influenced greatly by the canonical WNT signaling pathway. Genetically, the secreted protein Dickkopf (Dkk) family is known as an antagonist to the WNT. To clarify the role of DKK1 in the WNT signaling pathway in the colorectal carcinogenesis, we examined the DKK1 promoter methylation in CRC and analyze the relationship of expression level of DKK1 and MYC in relation with APC gene abnormalities. Methods: We integrated clinico-pathological and molecular findings of 41 cases of CRC. We adopted methylation-specific PCR, DNA sequencing, allelic loss analysis, quantitative RT-PCR, and MSI testing for genetic analyses. Results: CRCs with DKK1 promotor methylation were found in 10 cases (24.4%), which were located predominantly in the proximal colon and frequently showed findings of poorly differentiated adenocarcinoma or mucinous adenocarcinoma. Furthermore, colorectal cancers with DKK1 promotor methylation showed characteristics of microsatellite instability (MSI)-high (70%) and a BRAF mutation (40%), which are known as the CpG island methylator phenotype (CIMP). In the DKK1 promotor methylation group, the relative expression level of DKK1 mRNA was significantly reduced in comparison to the DKK1 promotor un-methylation group (p MYC expression in the DKK1 promotor methylation group was significantly elevated compared to that in the DKK1 promotor un-methylation group (p Conclusions: It is suggested that DKK1 is one of the regulators involved in MYC expression through the WNT signaling pathway and may have a negative effect on carcinogenesis of the colorectum without APC abnormalities.
VL  - 6
IS  - 1
ER  -

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