Map1lc3b and Sqstm1 Modulated Autophagy for Tumorigenesis and Prognosis in Certain Subsites of Oral Squamous Cell Carcinoma

Liu, Pei‐Feng; Chang, Hsueh-Wei; Cheng, Jin‐Shiung; Lee, Huai-Pao; Yen, Ching‐Yu; Tsai, Wei‐Lun; Cheng, Jiin‐Tsuey; Li, Yijing; Huang, Wei-Chieh; Lee, Cheng-Hsin; Ger, Luo-Pin; Shu, Chih‐Wen

doi:10.3390/jcm7120478

Cited by 27 publications

(35 citation statements)

References 40 publications

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“…ATG4B is the major autophagy-related protease required for activation of membrane-bound MAP1LC3-II, which is crucial for autophagosome elongation in mammalian cells. Our recent study showed that high protein levels of MAP1LC3-II puncta are linked to unfavorable DSS in TSCC but not in BMSCC [6]. In line with our present study, ATG4B expression was associated with poor DSS in TSCC patients, implying that ATG4B expression might be positively correlated with MAP1LC3-II puncta for autophagy induction and cause poor outcome in TSCC patients.…”

Section: Discussionsupporting

confidence: 90%

“…The TMA blocks were employed for immunohistochemistry staining as previously reported [6]. The TMA blocks were immersed in Tris-Ethylenediamine tetraacetic acid (EDTA) buffer (10 mM, pH 9.0) and boiled in a pressure boiler at 125 • C for 10 min for antigen retrieval of ATG4B and phospho-Ser383/392-ATG4B.…”

Section: Immunohistochemistry (Ihc)mentioning

confidence: 99%

“…Autophagy is a self-clearance pathway that eliminates abnormal organelles and proteins from cells and is essential for normal physiology. Dysfunction of autophagy is highly associated with many diseases, particularly cancer [5,6]. Autophagy is like a double-edged sword in cells.…”

Section: Introductionmentioning

confidence: 99%

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Association of ATG4B and Phosphorylated ATG4B Proteins with Tumorigenesis and Prognosis in Oral Squamous Cell Carcinoma

Liu

Chen

Cheng

et al. 2019

Cancers

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Oral squamous cell carcinoma (OSCC) is one of the major leading causes of cancer death worldwide due to the limited availability of biomarkers and therapeutic targets. Autophagy related protease 4B (ATG4B) is an essential protease for the autophagy machinery, and ATG4B phosphorylation at Ser383/392 increases its proteolytic activity. ATG4B expression and activation are crucial for cancer cell proliferation and invasion. However, the clinical relevance of ATG4B and phospho-Ser383/392-ATG4B for OSCC remains unknown, particularly in buccal mucosal SCC (BMSCC) and tongue SCC (TSCC). With a tissue microarray comprising specimens from 498 OSCC patients, including 179 BMSCC and 249 TSCC patients, we found that the protein levels of ATG4B and phospho-Ser383/392-ATG4B were elevated in the tumor tissues of BMSCC and TSCC compared with those in adjacent normal tissues. High protein levels of ATG4B were significantly associated with worse disease-specific survival (DSS) in OSCC patients, particularly in patients with tumors at advanced stages. In contrast, phospho-Ser383/392-ATG4B expression was correlated with poor disease-free survival (DFS) in TSCC patients. Moreover, ATG4B protein expression was positively correlated with phospho-Ser383/392-ATG4B expression in both BMSCC and TSCC. However, high coexpression levels of ATG4B and phospho-Ser383/392-ATG4B were associated with poor DFS only in TSCC patients, whereas they had no significant association with DSS in BMSCC and TSCC patients. In addition, silencing ATG4B with an antisense oligonucleotide (ASO) or small interfering RNA (siRNA) diminished cell proliferation of TW2.6 and SAS oral cancer cells. Further, knockdown of ATG4B reduced cell migration and invasion of oral cancer cells. Taken together, these findings suggest that ATG4B might be a biomarker for diagnosis/prognosis of OSCC and a potential therapeutic target for OSCC patients.

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Section: Discussionsupporting

confidence: 90%

Section: Immunohistochemistry (Ihc)mentioning

confidence: 99%

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Association of ATG4B and Phosphorylated ATG4B Proteins with Tumorigenesis and Prognosis in Oral Squamous Cell Carcinoma

Liu

Chen

Cheng

et al. 2019

Cancers

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“…Microtubule-associated protein-1 light chain 3 beta ( MAP1LC3B ) is significantly associated with adverse clinicopathological outcomes in some cancer types. Liu et al found that the expression levels of MAP1LC3B and SQSTM1 in tumor tissues were higher than those in adjacent normal tissues, suggesting that MAP1LC3B promoted the tumorigenesis and drug resistance of oral squamous cell carcinoma [ 42 ]. However, contrary to the above, high LC3 expression appears to be associated with reduced non-small-cell lung cancer invasiveness [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

Autophagy-Related Signature for Head and Neck Squamous Cell Carcinoma

Cheng

Yuan

2020

Disease Markers

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Background. Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignancies in the world, with low survival and poor quality of life. Autophagy-associated genes (ATGs) have been reported to be involved in the initiation and progression of malignancies. Here, we aimed to investigate the association between autophagy-associated genes and the outcomes in HNSCC patients. Methods. We obtained ATGs with prognostic values by analyzing the datasets from The Cancer Genome Atlas (TCGA) and Human Autophagy Database (HADb). The enrichment functions of autophagy differential genes were analyzed by Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). The Kaplan-Meier method was applied to the survival curve analysis. A prognostic autophagy-related gene signature was established, and its independence was verified. Results. We acquired a total of 529 samples and 232 ATGs; further, we identified 45 genes associated with prognosis and built a prognosis autophagy signature based on risk score of 15 genes. Patients were divided into two groups based on risk scores. The Kaplan-Meier curve illustrated that the survival rate of the high-risk group was significantly lower than that of the low-risk group in both the training group and validation group. The ROC curve revealed that the risk score had the highest AUC value in the 3rd and 5th years, reaching 0.703 and 0.724, which are higher than other risk factors such as gender, age, and TNM stage. The nomogram further confirmed its weight in the prognosis of HNSCC patients. Through KEGG and GO enrichment analyses, we observed that ATGs were involved in the tumorigenesis and invasion of tumor by various mediating pathways. We gained 3 hub genes (MAP1LC3B, FADD, and LAMP1) and further analyzed the survival curves, mutations, differential expressions, and their roles in tumors on the online websites. Conclusion. We identified a novel autophagy-related signature that may provide promising biomarker genes for the treatment and prognosis of HNSCC. We need to validate its prognostic value by applying it to the clinic.

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“…However, previous studies have been concentrated on the relationship between single or a few ARGs and OSCC prognosis. For instance, Liu PF et al found the coexpression of higher MAP1LC3B and SQSTM1 was significantly associated with poor disease-specific survival and disease-free survival in OSCC patients (23). In addition, another tissue microarray analysis suggested that ATG4B, an autophagy related protease, could be a potential biomarker for diagnosis and prognosis for OSCC (24).…”

Section: Introductionmentioning

confidence: 99%

Development and Validation of Autophagy-Related Gene Signature and Nomogram for Predicting Survival in Oral Squamous Cell Carcinoma

et al. 2020

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Background: Autophagy, a highly conserved self-digesting process, has been deeply involved in the development and progression of oral squamous cell carcinoma (OSCC). However, the prognostic value of autophagy-related genes (ARGs) for OSCC still remains unclear. Our study set out to develop a multigene expression signature based on ARGs for individualized prognosis assessment in OSCC patients. Methods: Based on The Cancer Genome Atlas (TCGA) database, we identified prognosis-related ARGs through univariate COX regression analysis. Then we performed the least absolute shrinkage and selection operator (LASSO) regression analysis to identify an optimal autophagy-related multigene signature with the subsequent validation in testing set, GSE41613 and GSE42743 datasets. Results: We identified 36 prognosis-related ARGs for OSCC. Subsequently, the multigene signature based on 13 prognostic ARGs was constructed and successfully divided OSCC patients into low and high-risk groups with significantly different overall survival in TCGA training set (p < 0.0001). The autophagy signature remained as an independent prognostic factor for OSCC in univariate and multivariate Cox regression analyses. The area under the curve (AUC) values of the receiver operating characteristic (ROC) curves for 1, 3, and 5-year survival were 0.758, 0.810, 0.798, respectively. Then the gene signature was validated in TCGA testing set, GSE41613 and GSE42743 datasets. Moreover, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and single-sample gene set enrichment analysis (ssGSEA) revealed the underlying biological characteristics and signaling pathways associated with this signature in OSCC. Finally, we constructed a nomogram by combining the gene signature with multiple clinical parameters (age, gender, TNM-stage, tobacco, and alcohol history). The concordance index (C-index) and calibration plots demonstrated favorable predictive performance of our nomogram.

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Map1lc3b and Sqstm1 Modulated Autophagy for Tumorigenesis and Prognosis in Certain Subsites of Oral Squamous Cell Carcinoma

Cited by 27 publications

References 40 publications

Association of ATG4B and Phosphorylated ATG4B Proteins with Tumorigenesis and Prognosis in Oral Squamous Cell Carcinoma

Association of ATG4B and Phosphorylated ATG4B Proteins with Tumorigenesis and Prognosis in Oral Squamous Cell Carcinoma

Autophagy-Related Signature for Head and Neck Squamous Cell Carcinoma

Development and Validation of Autophagy-Related Gene Signature and Nomogram for Predicting Survival in Oral Squamous Cell Carcinoma

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