PDGFA‐associated protein 1 is a novel target of c‐Myc and contributes to colorectal cancer initiation and progression
Abstract Background The mechanism underlying colorectal cancer (CRC) initiation and progression remains elusive, and overall survival is far from satisfactory. Previous studies have shown that PDGFA‐associated protein 1 (PDAP1) is upregulated in several cancers including CRC. Here, we aimed to ident...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-08-01
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| Series: | Cancer Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cac2.12322 |
| _version_ | 1818496819614711808 |
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| author | Hong‐Yong Cui Wei Wei Mei‐Rui Qian Ruo‐Fei Tian Xin Fu Hong‐Wei Li Gang Nan Ting Yang Peng Lin Xi Chen Yu‐Meng Zhu Bin Wang Xiu‐Xuan Sun Jian‐Hua Dou Jian‐Li Jiang Ling Li Shi‐Jie Wang Zhi‐Nan Chen |
| author_facet | Hong‐Yong Cui Wei Wei Mei‐Rui Qian Ruo‐Fei Tian Xin Fu Hong‐Wei Li Gang Nan Ting Yang Peng Lin Xi Chen Yu‐Meng Zhu Bin Wang Xiu‐Xuan Sun Jian‐Hua Dou Jian‐Li Jiang Ling Li Shi‐Jie Wang Zhi‐Nan Chen |
| author_sort | Hong‐Yong Cui |
| collection | DOAJ |
| description | Abstract Background The mechanism underlying colorectal cancer (CRC) initiation and progression remains elusive, and overall survival is far from satisfactory. Previous studies have shown that PDGFA‐associated protein 1 (PDAP1) is upregulated in several cancers including CRC. Here, we aimed to identify the cause and consequence of PDAP1 dysregulation in CRC and evaluate its role as a potential therapeutic target. Methods Multi‐omics data analysis was performed to identify potential key players in CRC initiation and progression. Immunohistochemistry (IHC) staining was applied to determine the expression pattern of PDAP1 in CRC tissues. Pdap1 conditional knockout mice were used to establish colitis and CRC mouse models. RNA sequencing, a phosphoprotein antibody array, western blotting, histological analysis, 5‐bromo‐2′‐deoxyuridine (BrdU) incorporation assay, and interactome analysis were applied to identify the underlying mechanisms of PDAP1. A human patient‐derived xenograft (PDX) model was used to assess the potential of PDAP1 as a therapeutic target. Results PDAP1 was identified as a potential key player in CRC development using multi‐omics data analysis. PDAP1 was overexpressed in CRC cells and correlated with reduced overall survival. Further investigation showed that PDAP1 was critical for the regulation of cell proliferation, migration, invasion, and metastasis. Significantly, depletion of Pdap1 in intestinal epithelial cells impaired mucosal restitution in dextran sulfate sodium salt‐induced colitis and inhibited tumor initiation and growth in colitis‐associated cancers. Mechanistic studies showed that c‐Myc directly transactivated PDAP1, which contributed to the high PDAP1 expression in CRC cells. PDAP1 interacted with the juxtamembrane domain of epidermal growth factor receptor (EGFR) and facilitated EGFR‐mitogen‐activated protein kinase (MAPK) signaling activation, which resulted in FOS‐related antigen 1 (FRA‐1) expression, thereby facilitating CRC progression. Notably, silencing of PDAP1 could hinder the growth of patient‐derived xenografts that sustain high PDAP1 levels. Conclusions PDAP1 facilitates mucosal restitution and carcinogenesis in colitis‐associated cancer. c‐Myc‐driven upregulation of PDAP1 promotes proliferation, migration, invasion, and metastasis of CRC cells via the EGFR‐MAPK‐FRA‐1 signaling axis. These findings indicated that PDAP1 inhibition is warranted for CRC patients with PDAP1 overexpression. |
| first_indexed | 2024-12-10T18:37:45Z |
| format | Article |
| id | doaj.art-ced8328fe33441678208f1ccfb5e4ab6 |
| institution | Directory Open Access Journal |
| issn | 2523-3548 |
| language | English |
| last_indexed | 2024-12-10T18:37:45Z |
| publishDate | 2022-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Communications |
| spelling | doaj.art-ced8328fe33441678208f1ccfb5e4ab62022-12-22T01:37:45ZengWileyCancer Communications2523-35482022-08-0142875076710.1002/cac2.12322PDGFA‐associated protein 1 is a novel target of c‐Myc and contributes to colorectal cancer initiation and progressionHong‐Yong Cui0Wei Wei1Mei‐Rui Qian2Ruo‐Fei Tian3Xin Fu4Hong‐Wei Li5Gang Nan6Ting Yang7Peng Lin8Xi Chen9Yu‐Meng Zhu10Bin Wang11Xiu‐Xuan Sun12Jian‐Hua Dou13Jian‐Li Jiang14Ling Li15Shi‐Jie Wang16Zhi‐Nan Chen17National Translational Science Center for Molecular Medicine & Department of Cell Biology Fourth Military Medical University Xi'an Shaanxi 710032 P. R. ChinaNational Translational Science Center for Molecular Medicine & Department of Cell Biology Fourth Military Medical University Xi'an Shaanxi 710032 P. R. ChinaNational Translational Science Center for Molecular Medicine & Department of Cell Biology Fourth Military Medical University Xi'an Shaanxi 710032 P. R. ChinaNational Translational Science Center for Molecular Medicine & Department of Cell Biology Fourth Military Medical University Xi'an Shaanxi 710032 P. R. ChinaNational Translational Science Center for Molecular Medicine & Department of Cell Biology Fourth Military Medical University Xi'an Shaanxi 710032 P. R. ChinaState Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases Xijing Hospital of Digestive Diseases Fourth Military Medical University Xi'an Shaanxi 710032 P. R. ChinaNational Translational Science Center for Molecular Medicine & Department of Cell Biology Fourth Military Medical University Xi'an Shaanxi 710032 P. R. ChinaNational Translational Science Center for Molecular Medicine & Department of Cell Biology Fourth Military Medical University Xi'an Shaanxi 710032 P. R. ChinaNational Translational Science Center for Molecular Medicine & Department of Cell Biology Fourth Military Medical University Xi'an Shaanxi 710032 P. R. ChinaKey Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education College of Chemistry and Materials Science Northwest University Xi'an Shaanxi 710127 P. R. ChinaNational Translational Science Center for Molecular Medicine & Department of Cell Biology Fourth Military Medical University Xi'an Shaanxi 710032 P. R. ChinaNational Translational Science Center for Molecular Medicine & Department of Cell Biology Fourth Military Medical University Xi'an Shaanxi 710032 P. R. ChinaNational Translational Science Center for Molecular Medicine & Department of Cell Biology Fourth Military Medical University Xi'an Shaanxi 710032 P. R. ChinaState Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases Xijing Hospital of Digestive Diseases Fourth Military Medical University Xi'an Shaanxi 710032 P. R. ChinaNational Translational Science Center for Molecular Medicine & Department of Cell Biology Fourth Military Medical University Xi'an Shaanxi 710032 P. R. ChinaNational Translational Science Center for Molecular Medicine & Department of Cell Biology Fourth Military Medical University Xi'an Shaanxi 710032 P. R. ChinaNational Translational Science Center for Molecular Medicine & Department of Cell Biology Fourth Military Medical University Xi'an Shaanxi 710032 P. R. ChinaNational Translational Science Center for Molecular Medicine & Department of Cell Biology Fourth Military Medical University Xi'an Shaanxi 710032 P. R. ChinaAbstract Background The mechanism underlying colorectal cancer (CRC) initiation and progression remains elusive, and overall survival is far from satisfactory. Previous studies have shown that PDGFA‐associated protein 1 (PDAP1) is upregulated in several cancers including CRC. Here, we aimed to identify the cause and consequence of PDAP1 dysregulation in CRC and evaluate its role as a potential therapeutic target. Methods Multi‐omics data analysis was performed to identify potential key players in CRC initiation and progression. Immunohistochemistry (IHC) staining was applied to determine the expression pattern of PDAP1 in CRC tissues. Pdap1 conditional knockout mice were used to establish colitis and CRC mouse models. RNA sequencing, a phosphoprotein antibody array, western blotting, histological analysis, 5‐bromo‐2′‐deoxyuridine (BrdU) incorporation assay, and interactome analysis were applied to identify the underlying mechanisms of PDAP1. A human patient‐derived xenograft (PDX) model was used to assess the potential of PDAP1 as a therapeutic target. Results PDAP1 was identified as a potential key player in CRC development using multi‐omics data analysis. PDAP1 was overexpressed in CRC cells and correlated with reduced overall survival. Further investigation showed that PDAP1 was critical for the regulation of cell proliferation, migration, invasion, and metastasis. Significantly, depletion of Pdap1 in intestinal epithelial cells impaired mucosal restitution in dextran sulfate sodium salt‐induced colitis and inhibited tumor initiation and growth in colitis‐associated cancers. Mechanistic studies showed that c‐Myc directly transactivated PDAP1, which contributed to the high PDAP1 expression in CRC cells. PDAP1 interacted with the juxtamembrane domain of epidermal growth factor receptor (EGFR) and facilitated EGFR‐mitogen‐activated protein kinase (MAPK) signaling activation, which resulted in FOS‐related antigen 1 (FRA‐1) expression, thereby facilitating CRC progression. Notably, silencing of PDAP1 could hinder the growth of patient‐derived xenografts that sustain high PDAP1 levels. Conclusions PDAP1 facilitates mucosal restitution and carcinogenesis in colitis‐associated cancer. c‐Myc‐driven upregulation of PDAP1 promotes proliferation, migration, invasion, and metastasis of CRC cells via the EGFR‐MAPK‐FRA‐1 signaling axis. These findings indicated that PDAP1 inhibition is warranted for CRC patients with PDAP1 overexpression.https://doi.org/10.1002/cac2.12322carcinogenesiscolorectal cancerFRA‐1PDAP1c‐Myc |
| spellingShingle | Hong‐Yong Cui Wei Wei Mei‐Rui Qian Ruo‐Fei Tian Xin Fu Hong‐Wei Li Gang Nan Ting Yang Peng Lin Xi Chen Yu‐Meng Zhu Bin Wang Xiu‐Xuan Sun Jian‐Hua Dou Jian‐Li Jiang Ling Li Shi‐Jie Wang Zhi‐Nan Chen PDGFA‐associated protein 1 is a novel target of c‐Myc and contributes to colorectal cancer initiation and progression Cancer Communications carcinogenesis colorectal cancer FRA‐1 PDAP1 c‐Myc |
| title | PDGFA‐associated protein 1 is a novel target of c‐Myc and contributes to colorectal cancer initiation and progression |
| title_full | PDGFA‐associated protein 1 is a novel target of c‐Myc and contributes to colorectal cancer initiation and progression |
| title_fullStr | PDGFA‐associated protein 1 is a novel target of c‐Myc and contributes to colorectal cancer initiation and progression |
| title_full_unstemmed | PDGFA‐associated protein 1 is a novel target of c‐Myc and contributes to colorectal cancer initiation and progression |
| title_short | PDGFA‐associated protein 1 is a novel target of c‐Myc and contributes to colorectal cancer initiation and progression |
| title_sort | pdgfa associated protein 1 is a novel target of c myc and contributes to colorectal cancer initiation and progression |
| topic | carcinogenesis colorectal cancer FRA‐1 PDAP1 c‐Myc |
| url | https://doi.org/10.1002/cac2.12322 |
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