DPEP1 promotes drug resistance in colon cancer cells by forming a positive feedback loop with ASCL2
Abstract Background Drug resistance is an important factor affecting the efficacy of chemotherapy in patients with colon cancer. However, clinical markers for diagnosing drug resistance of tumor cells are not only a few in number, but also low in specificity, and the mechanism of action of tumor cel...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-01-01
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| Series: | Cancer Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cam4.4926 |
| _version_ | 1797950856383954944 |
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| author | Cheng Zeng Guoping Qi Ying Shen Wenjing Li Qi Zhu Chunxia Yang Jianzhong Deng Wenbin Lu Qian Liu Jianhua Jin |
| author_facet | Cheng Zeng Guoping Qi Ying Shen Wenjing Li Qi Zhu Chunxia Yang Jianzhong Deng Wenbin Lu Qian Liu Jianhua Jin |
| author_sort | Cheng Zeng |
| collection | DOAJ |
| description | Abstract Background Drug resistance is an important factor affecting the efficacy of chemotherapy in patients with colon cancer. However, clinical markers for diagnosing drug resistance of tumor cells are not only a few in number, but also low in specificity, and the mechanism of action of tumor cell drug resistance remains unclear. Methods Dipeptidase 1 (DPEP1) expression was analyzed using the cancer genome atlas (TCGA) and genotype‐Tissue Expression pan‐cancer data. Survival analysis was performed using the survival package in R software to assess the prognostic value of DPEP1 expression in colon cancer. Correlation and Venn analyses were adopted to identify key genes. Immunohistochemistry, western blot, qRT–PCR, Co‐immunoprecipitation, and dual‐luciferase reporter experiments were carried out to explore the underlying associations between DPEP1 and Achaete scute‐like 2 (ASCL2). MTT assays were used to evaluate the role of DPEP1 and ASCL2 in colon cancer drug resistance. Results DPEP1 was highly expressed in colon cancer tissues. DPEP1 expression correlated negatively with disease‐specific survival but not with overall survival. Bioinformatics analysis and experiments showed that the expressions of DPEP1 and ASCL2 in colon cancer tissues were markedly positively correlated. Mechanistic research indicated that DPEP1 enhanced the stability of protein ASCL2 by inhibiting its ubiquitination‐mediated degradation. In turn, ASCL2 functioned as a transcription factor to activate the transcriptional activity of the DPEP1 gene and boost its expression. Furthermore, DPEP1 also could enhance the expression of colon cancer stem cell markers (LGR5, CD133, and CD44), which strengthened the tolerance of colon cancer cells to chemotherapy drugs. Conclusions Our findings reveal that the DPEP1 enhances the stemness of tumor cells by forming a positive feedback loop with ASCL2 to improve resistance to chemotherapy drugs. |
| first_indexed | 2024-04-10T22:21:40Z |
| format | Article |
| id | doaj.art-2134885520c6466da9b567c91a0e9aac |
| institution | Directory Open Access Journal |
| issn | 2045-7634 |
| language | English |
| last_indexed | 2024-04-10T22:21:40Z |
| publishDate | 2023-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj.art-2134885520c6466da9b567c91a0e9aac2023-01-17T17:10:25ZengWileyCancer Medicine2045-76342023-01-0112141242410.1002/cam4.4926DPEP1 promotes drug resistance in colon cancer cells by forming a positive feedback loop with ASCL2Cheng Zeng0Guoping Qi1Ying Shen2Wenjing Li3Qi Zhu4Chunxia Yang5Jianzhong Deng6Wenbin Lu7Qian Liu8Jianhua Jin9Department of Oncology Wujin Hospital Affiliated with Jiangsu University Changzhou Jiangsu Province ChinaDepartment of Oncology Wujin Hospital Affiliated with Jiangsu University Changzhou Jiangsu Province ChinaDepartment of Oncology Wujin Hospital Affiliated with Jiangsu University Changzhou Jiangsu Province ChinaDepartment of Oncology Wujin Hospital Affiliated with Jiangsu University Changzhou Jiangsu Province ChinaDepartment of Oncology Wujin Hospital Affiliated with Jiangsu University Changzhou Jiangsu Province ChinaDepartment of Oncology Wujin Hospital Affiliated with Jiangsu University Changzhou Jiangsu Province ChinaDepartment of Oncology Wujin Hospital Affiliated with Jiangsu University Changzhou Jiangsu Province ChinaDepartment of Oncology Wujin Hospital Affiliated with Jiangsu University Changzhou Jiangsu Province ChinaDepartment of Oncology Wujin Hospital Affiliated with Jiangsu University Changzhou Jiangsu Province ChinaDepartment of Oncology Wujin Hospital Affiliated with Jiangsu University Changzhou Jiangsu Province ChinaAbstract Background Drug resistance is an important factor affecting the efficacy of chemotherapy in patients with colon cancer. However, clinical markers for diagnosing drug resistance of tumor cells are not only a few in number, but also low in specificity, and the mechanism of action of tumor cell drug resistance remains unclear. Methods Dipeptidase 1 (DPEP1) expression was analyzed using the cancer genome atlas (TCGA) and genotype‐Tissue Expression pan‐cancer data. Survival analysis was performed using the survival package in R software to assess the prognostic value of DPEP1 expression in colon cancer. Correlation and Venn analyses were adopted to identify key genes. Immunohistochemistry, western blot, qRT–PCR, Co‐immunoprecipitation, and dual‐luciferase reporter experiments were carried out to explore the underlying associations between DPEP1 and Achaete scute‐like 2 (ASCL2). MTT assays were used to evaluate the role of DPEP1 and ASCL2 in colon cancer drug resistance. Results DPEP1 was highly expressed in colon cancer tissues. DPEP1 expression correlated negatively with disease‐specific survival but not with overall survival. Bioinformatics analysis and experiments showed that the expressions of DPEP1 and ASCL2 in colon cancer tissues were markedly positively correlated. Mechanistic research indicated that DPEP1 enhanced the stability of protein ASCL2 by inhibiting its ubiquitination‐mediated degradation. In turn, ASCL2 functioned as a transcription factor to activate the transcriptional activity of the DPEP1 gene and boost its expression. Furthermore, DPEP1 also could enhance the expression of colon cancer stem cell markers (LGR5, CD133, and CD44), which strengthened the tolerance of colon cancer cells to chemotherapy drugs. Conclusions Our findings reveal that the DPEP1 enhances the stemness of tumor cells by forming a positive feedback loop with ASCL2 to improve resistance to chemotherapy drugs.https://doi.org/10.1002/cam4.4926ASCL2bioinformaticscolon cancerDPEP1drug resistance |
| spellingShingle | Cheng Zeng Guoping Qi Ying Shen Wenjing Li Qi Zhu Chunxia Yang Jianzhong Deng Wenbin Lu Qian Liu Jianhua Jin DPEP1 promotes drug resistance in colon cancer cells by forming a positive feedback loop with ASCL2 Cancer Medicine ASCL2 bioinformatics colon cancer DPEP1 drug resistance |
| title | DPEP1 promotes drug resistance in colon cancer cells by forming a positive feedback loop with ASCL2 |
| title_full | DPEP1 promotes drug resistance in colon cancer cells by forming a positive feedback loop with ASCL2 |
| title_fullStr | DPEP1 promotes drug resistance in colon cancer cells by forming a positive feedback loop with ASCL2 |
| title_full_unstemmed | DPEP1 promotes drug resistance in colon cancer cells by forming a positive feedback loop with ASCL2 |
| title_short | DPEP1 promotes drug resistance in colon cancer cells by forming a positive feedback loop with ASCL2 |
| title_sort | dpep1 promotes drug resistance in colon cancer cells by forming a positive feedback loop with ascl2 |
| topic | ASCL2 bioinformatics colon cancer DPEP1 drug resistance |
| url | https://doi.org/10.1002/cam4.4926 |
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