ATG4B and pS383/392-ATG4B serve as potential biomarkers and therapeutic targets of colorectal cancer
Abstract Background Autophagy related protease 4B (ATG4B) is a protease required for autophagy processing, which is strongly implicated in cancer progression. Phosphorylation of ATG4B is crucial for activation of its protease activity. However, little is known about the relationship of ATG4B and i...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-04-01
|
| Series: | Cancer Cell International |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12935-023-02909-7 |
| _version_ | 1797845719608983552 |
|---|---|
| author | Wan-Hsiang Hu Ting-Ting Liu Pei-Feng Liu Paul Morgan I-Ling Lin Wei-Lun Tsai Yi-Yun Cheng Ang-Tsen Hsieh Tsung-Hui Hu Chih-Wen Shu |
| author_facet | Wan-Hsiang Hu Ting-Ting Liu Pei-Feng Liu Paul Morgan I-Ling Lin Wei-Lun Tsai Yi-Yun Cheng Ang-Tsen Hsieh Tsung-Hui Hu Chih-Wen Shu |
| author_sort | Wan-Hsiang Hu |
| collection | DOAJ |
| description | Abstract Background Autophagy related protease 4B (ATG4B) is a protease required for autophagy processing, which is strongly implicated in cancer progression. Phosphorylation of ATG4B is crucial for activation of its protease activity. However, little is known about the relationship of ATG4B and its phosphorylated form at Ser 383 and 392 sites (pS383/392-ATG4B), with clinical outcomes, particularly in colorectal cancer (CRC). Methods The ATG4B gene expression in CRC patients was obtained from The Cancer Genome Atlas (TCGA) database to analyze its clinical relevance. Tissue microarrays composed of 118 CRC patient specimens were used to determine the associations of ATG4B and pS383/392-ATG4B protein levels with prognosis. The biological functions of ATG4B in CRC cells were inspected with cell proliferation, mobility and spheroid culture assays. Results ATG4B gene expression was elevated in tumor tissues of CRC patients compared to that in adjacent normal tissues and high level of ATG4B expression was associated with poor survival. Similarly, protein levels of ATG4B and pS383/392-ATG4B were highly correlated with worse overall survival and disease-free survival. Stratification analysis results showed that high level of ATG4B had significantly higher risk of mortality in males and elderly patients compared to those female patients and patients 60 years or younger. In contrast, multivariate Cox’s regression analysis indicated that high level of pS383/392-ATG4B was significantly linked to unfavorable overall survival and disease-free survival of males and elderly patients, whereas, it had no correlation with female patients and patients 60 years or younger. Moreover, high level of ATG4B was positively associated with increased mortality risk in patients with advanced AJCC stages (III and IV) and lymph node invasion (N1 and N2) for both overall survival and disease-free survival. Nevertheless, high level of pS383/392-ATG4B was positively correlated with increased mortality risk in patients with early AJCC stages (I and II) and without lymph node invasion (N0). In addition, silencing ATG4B attenuated migration, invasion, and further enhanced the cytotoxic effects of chemotherapeutic drugs in two and three-dimensional cultures of CRC cells. Conclusions Our results suggest that ATG4B and pS383/392-ATG4B might be suitable biomarkers and therapeutic targets for CRC. |
| first_indexed | 2024-04-09T17:43:30Z |
| format | Article |
| id | doaj.art-0be8ee22e46d479483caa93fbdd655fa |
| institution | Directory Open Access Journal |
| issn | 1475-2867 |
| language | English |
| last_indexed | 2024-04-09T17:43:30Z |
| publishDate | 2023-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer Cell International |
| spelling | doaj.art-0be8ee22e46d479483caa93fbdd655fa2023-04-16T11:25:52ZengBMCCancer Cell International1475-28672023-04-0123111710.1186/s12935-023-02909-7ATG4B and pS383/392-ATG4B serve as potential biomarkers and therapeutic targets of colorectal cancerWan-Hsiang Hu0Ting-Ting Liu1Pei-Feng Liu2Paul Morgan3I-Ling Lin4Wei-Lun Tsai5Yi-Yun Cheng6Ang-Tsen Hsieh7Tsung-Hui Hu8Chih-Wen Shu9Department of Colorectal Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of MedicineDepartment of Pathology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of MedicineDepartment of Biomedical Science and Environmental Biology, Kaohsiung Medical UniversityIcahn School of Medicine at Mount SinaiDepartment of Medical Laboratory Science and Biotechnology, Kaohsiung Medical UniversityDepartment of Internal Medicine, Kaohsiung Veterans General HospitalInnovative Incubation Center, Praexisio Taiwain Inc, National Tsing Hua UniversityInstitute of Biopharmaceutical Sciences, National Sun Yat-sen UniversityDivision of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of MedicineInstitute of Biopharmaceutical Sciences, National Sun Yat-sen UniversityAbstract Background Autophagy related protease 4B (ATG4B) is a protease required for autophagy processing, which is strongly implicated in cancer progression. Phosphorylation of ATG4B is crucial for activation of its protease activity. However, little is known about the relationship of ATG4B and its phosphorylated form at Ser 383 and 392 sites (pS383/392-ATG4B), with clinical outcomes, particularly in colorectal cancer (CRC). Methods The ATG4B gene expression in CRC patients was obtained from The Cancer Genome Atlas (TCGA) database to analyze its clinical relevance. Tissue microarrays composed of 118 CRC patient specimens were used to determine the associations of ATG4B and pS383/392-ATG4B protein levels with prognosis. The biological functions of ATG4B in CRC cells were inspected with cell proliferation, mobility and spheroid culture assays. Results ATG4B gene expression was elevated in tumor tissues of CRC patients compared to that in adjacent normal tissues and high level of ATG4B expression was associated with poor survival. Similarly, protein levels of ATG4B and pS383/392-ATG4B were highly correlated with worse overall survival and disease-free survival. Stratification analysis results showed that high level of ATG4B had significantly higher risk of mortality in males and elderly patients compared to those female patients and patients 60 years or younger. In contrast, multivariate Cox’s regression analysis indicated that high level of pS383/392-ATG4B was significantly linked to unfavorable overall survival and disease-free survival of males and elderly patients, whereas, it had no correlation with female patients and patients 60 years or younger. Moreover, high level of ATG4B was positively associated with increased mortality risk in patients with advanced AJCC stages (III and IV) and lymph node invasion (N1 and N2) for both overall survival and disease-free survival. Nevertheless, high level of pS383/392-ATG4B was positively correlated with increased mortality risk in patients with early AJCC stages (I and II) and without lymph node invasion (N0). In addition, silencing ATG4B attenuated migration, invasion, and further enhanced the cytotoxic effects of chemotherapeutic drugs in two and three-dimensional cultures of CRC cells. Conclusions Our results suggest that ATG4B and pS383/392-ATG4B might be suitable biomarkers and therapeutic targets for CRC.https://doi.org/10.1186/s12935-023-02909-7ATG4BPhosphorylationPrognosiscancer |
| spellingShingle | Wan-Hsiang Hu Ting-Ting Liu Pei-Feng Liu Paul Morgan I-Ling Lin Wei-Lun Tsai Yi-Yun Cheng Ang-Tsen Hsieh Tsung-Hui Hu Chih-Wen Shu ATG4B and pS383/392-ATG4B serve as potential biomarkers and therapeutic targets of colorectal cancer Cancer Cell International ATG4B Phosphorylation Prognosis cancer |
| title | ATG4B and pS383/392-ATG4B serve as potential biomarkers and therapeutic targets of colorectal cancer |
| title_full | ATG4B and pS383/392-ATG4B serve as potential biomarkers and therapeutic targets of colorectal cancer |
| title_fullStr | ATG4B and pS383/392-ATG4B serve as potential biomarkers and therapeutic targets of colorectal cancer |
| title_full_unstemmed | ATG4B and pS383/392-ATG4B serve as potential biomarkers and therapeutic targets of colorectal cancer |
| title_short | ATG4B and pS383/392-ATG4B serve as potential biomarkers and therapeutic targets of colorectal cancer |
| title_sort | atg4b and ps383 392 atg4b serve as potential biomarkers and therapeutic targets of colorectal cancer |
| topic | ATG4B Phosphorylation Prognosis cancer |
| url | https://doi.org/10.1186/s12935-023-02909-7 |
| work_keys_str_mv | AT wanhsianghu atg4bandps383392atg4bserveaspotentialbiomarkersandtherapeutictargetsofcolorectalcancer AT tingtingliu atg4bandps383392atg4bserveaspotentialbiomarkersandtherapeutictargetsofcolorectalcancer AT peifengliu atg4bandps383392atg4bserveaspotentialbiomarkersandtherapeutictargetsofcolorectalcancer AT paulmorgan atg4bandps383392atg4bserveaspotentialbiomarkersandtherapeutictargetsofcolorectalcancer AT ilinglin atg4bandps383392atg4bserveaspotentialbiomarkersandtherapeutictargetsofcolorectalcancer AT weiluntsai atg4bandps383392atg4bserveaspotentialbiomarkersandtherapeutictargetsofcolorectalcancer AT yiyuncheng atg4bandps383392atg4bserveaspotentialbiomarkersandtherapeutictargetsofcolorectalcancer AT angtsenhsieh atg4bandps383392atg4bserveaspotentialbiomarkersandtherapeutictargetsofcolorectalcancer AT tsunghuihu atg4bandps383392atg4bserveaspotentialbiomarkersandtherapeutictargetsofcolorectalcancer AT chihwenshu atg4bandps383392atg4bserveaspotentialbiomarkersandtherapeutictargetsofcolorectalcancer |