Polymeric immunoglobulin receptor suppresses colorectal cancer through the AKT-FOXO3/4 axis by downregulating LAMB3 expression
Colorectal cancer (CRC) remains one of the most common malignancies worldwide and its mechanism is unclear. Polymeric immunoglobulin receptor (PIGR) which plays an important role in mucosal immunity is widely expressed in the mucosal epithelium and is dysregulated in different tumors. However, the r...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-08-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.924988/full |
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| author | Ding Zhang Hao Huang Ting Zheng Lei Zhang Binbin Cui Yanlong Liu Shiheng Tan Liyuan Zhao Tian Tian Lijing Gao Qingzhen Fu Zesong Cheng Yashuang Zhao |
| author_facet | Ding Zhang Hao Huang Ting Zheng Lei Zhang Binbin Cui Yanlong Liu Shiheng Tan Liyuan Zhao Tian Tian Lijing Gao Qingzhen Fu Zesong Cheng Yashuang Zhao |
| author_sort | Ding Zhang |
| collection | DOAJ |
| description | Colorectal cancer (CRC) remains one of the most common malignancies worldwide and its mechanism is unclear. Polymeric immunoglobulin receptor (PIGR) which plays an important role in mucosal immunity is widely expressed in the mucosal epithelium and is dysregulated in different tumors. However, the role and underlying mechanisms of PIGR in CRC remain unclear. Here, we demonstrated that PIGR was hypermethylated and downregulated in our cohort (N = 272), and these features were associated with reduced overall survival in patients (HRmethylation 1.61, 95% CI [1.11-2.33]). These findings were validated by external TCGA and GEO data. Moreover, PIGR overexpression inhibits CRC cell malignant phenotypes in vitro and impedes CRC cells growth in male BALB/c nude mice. Mechanistically, PIGR physically associates with RE1 silencing transcription factor (REST) and blocks the transcription of laminin subunit beta 3 (LAMB3). Subsequently, the AKT-FOXO3/4 axis was suppressed by downregulated LAMB3. In the drug sensitive assay, PIGR-overexpressing cells were more sensitive to cisplatin and gemcitabine. Together, PIGR may serve as a powerful prognostic biomarker and putative tumor suppressor by suppressing the AKT-FOXO3/4 axis by downregulating LAMB3 in CRC. Our study may offer a novel therapeutic strategy for treating CRC patients who highly express PIGR with cisplatin and gemcitabine. |
| first_indexed | 2024-04-11T21:55:26Z |
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| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-11T21:55:26Z |
| publishDate | 2022-08-01 |
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| series | Frontiers in Oncology |
| spelling | doaj.art-f993160541a24807b12ed2210521dbd32022-12-22T04:01:07ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-08-011210.3389/fonc.2022.924988924988Polymeric immunoglobulin receptor suppresses colorectal cancer through the AKT-FOXO3/4 axis by downregulating LAMB3 expressionDing Zhang0Hao Huang1Ting Zheng2Lei Zhang3Binbin Cui4Yanlong Liu5Shiheng Tan6Liyuan Zhao7Tian Tian8Lijing Gao9Qingzhen Fu10Zesong Cheng11Yashuang Zhao12Department of Epidemiology, School of Public Health, NHC Key Laboratory of Etiology and Epidemiology (23618504), Harbin Medical University, Harbin, ChinaDepartment of Epidemiology, School of Public Health, NHC Key Laboratory of Etiology and Epidemiology (23618504), Harbin Medical University, Harbin, ChinaDepartment of Epidemiology, School of Public Health, NHC Key Laboratory of Etiology and Epidemiology (23618504), Harbin Medical University, Harbin, ChinaDepartment of Epidemiology, School of Public Health, NHC Key Laboratory of Etiology and Epidemiology (23618504), Harbin Medical University, Harbin, ChinaDepartment of Colorectal Surgery, The Third Affiliated Hospital of Harbin Medical University, Harbin, ChinaDepartment of Colorectal Surgery, The Third Affiliated Hospital of Harbin Medical University, Harbin, ChinaDepartment of Epidemiology, School of Public Health, NHC Key Laboratory of Etiology and Epidemiology (23618504), Harbin Medical University, Harbin, ChinaDepartment of Epidemiology, School of Public Health, NHC Key Laboratory of Etiology and Epidemiology (23618504), Harbin Medical University, Harbin, ChinaDepartment of Epidemiology, School of Public Health, NHC Key Laboratory of Etiology and Epidemiology (23618504), Harbin Medical University, Harbin, ChinaDepartment of Epidemiology, School of Public Health, NHC Key Laboratory of Etiology and Epidemiology (23618504), Harbin Medical University, Harbin, ChinaDepartment of Epidemiology, School of Public Health, NHC Key Laboratory of Etiology and Epidemiology (23618504), Harbin Medical University, Harbin, ChinaDepartment of Epidemiology, School of Public Health, NHC Key Laboratory of Etiology and Epidemiology (23618504), Harbin Medical University, Harbin, ChinaDepartment of Epidemiology, School of Public Health, NHC Key Laboratory of Etiology and Epidemiology (23618504), Harbin Medical University, Harbin, ChinaColorectal cancer (CRC) remains one of the most common malignancies worldwide and its mechanism is unclear. Polymeric immunoglobulin receptor (PIGR) which plays an important role in mucosal immunity is widely expressed in the mucosal epithelium and is dysregulated in different tumors. However, the role and underlying mechanisms of PIGR in CRC remain unclear. Here, we demonstrated that PIGR was hypermethylated and downregulated in our cohort (N = 272), and these features were associated with reduced overall survival in patients (HRmethylation 1.61, 95% CI [1.11-2.33]). These findings were validated by external TCGA and GEO data. Moreover, PIGR overexpression inhibits CRC cell malignant phenotypes in vitro and impedes CRC cells growth in male BALB/c nude mice. Mechanistically, PIGR physically associates with RE1 silencing transcription factor (REST) and blocks the transcription of laminin subunit beta 3 (LAMB3). Subsequently, the AKT-FOXO3/4 axis was suppressed by downregulated LAMB3. In the drug sensitive assay, PIGR-overexpressing cells were more sensitive to cisplatin and gemcitabine. Together, PIGR may serve as a powerful prognostic biomarker and putative tumor suppressor by suppressing the AKT-FOXO3/4 axis by downregulating LAMB3 in CRC. Our study may offer a novel therapeutic strategy for treating CRC patients who highly express PIGR with cisplatin and gemcitabine.https://www.frontiersin.org/articles/10.3389/fonc.2022.924988/fullcolorectal cancerpolymeric immunoglobulin receptorprognostic markerAKT-FOXO3/4 axismethylation-driven gene |
| spellingShingle | Ding Zhang Hao Huang Ting Zheng Lei Zhang Binbin Cui Yanlong Liu Shiheng Tan Liyuan Zhao Tian Tian Lijing Gao Qingzhen Fu Zesong Cheng Yashuang Zhao Polymeric immunoglobulin receptor suppresses colorectal cancer through the AKT-FOXO3/4 axis by downregulating LAMB3 expression Frontiers in Oncology colorectal cancer polymeric immunoglobulin receptor prognostic marker AKT-FOXO3/4 axis methylation-driven gene |
| title | Polymeric immunoglobulin receptor suppresses colorectal cancer through the AKT-FOXO3/4 axis by downregulating LAMB3 expression |
| title_full | Polymeric immunoglobulin receptor suppresses colorectal cancer through the AKT-FOXO3/4 axis by downregulating LAMB3 expression |
| title_fullStr | Polymeric immunoglobulin receptor suppresses colorectal cancer through the AKT-FOXO3/4 axis by downregulating LAMB3 expression |
| title_full_unstemmed | Polymeric immunoglobulin receptor suppresses colorectal cancer through the AKT-FOXO3/4 axis by downregulating LAMB3 expression |
| title_short | Polymeric immunoglobulin receptor suppresses colorectal cancer through the AKT-FOXO3/4 axis by downregulating LAMB3 expression |
| title_sort | polymeric immunoglobulin receptor suppresses colorectal cancer through the akt foxo3 4 axis by downregulating lamb3 expression |
| topic | colorectal cancer polymeric immunoglobulin receptor prognostic marker AKT-FOXO3/4 axis methylation-driven gene |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.924988/full |
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