Dataset Information

Prognostic Value of Autophagy-related Proteins in Human Gastric Cancer.

ABSTRACT:

Purpose

Autophagy-related proteins (ATG) play a crucial role in autophagy. Recently, the functions of autophagy in cancer have been gathering attention. However, the prognostic value of ATGs in gastric cancer (GC) has not been explored.

Methods

The Kaplan-Meier plotter (KM plotter) online database was used to examine the value of ATGs gene expression levels in overall survival (OS) prediction in GC patients with different clinical stage, differentiation, gender, HER2 status, and therapeutic strategy. In vitro experiments applied VE-822, an effective GC treatment, to assess cell migration and proliferation in gastric mucosa epithelial cells, and real-time PCR was used to measure alterations of autophagy-related gene expression.

Results

High ATG3, ATG4C, ATG5, and ATG10 mRNA levels were associated with good OS, while increased ATG4B, ATG7, ATG12, ATG16L1, and TECPR1 mRNA levels related to unfavorable OS in patients with GC. ATG12 overexpression had different effects on OS due to high levels of heterogeneity. High ATG12 expression was correlated with good OS in female patients with GC and with bad OS for male patients. Additionally, the increased ATG12 expression was more likely to get a satisfactory OS in patients who underwent surgery alone but was associated with poor OS for patients treated with 5-FU adjuvant. In addition, elevated TECPR1 expression was related to favorable OS for patients with poorly differentiated type, while for patients with moderate differentiation, it was relevant to poor OS. The in vitro experiments showed that berzosertib could significantly inhibit the migration and proliferation of human gastric mucosa epithelial cells, and further real-time PCR assessment of ATG expressions partially coincided with the bioinformation analysis above.

Conclusion

These results indicate that individual ATGs have unique prognostic significance interpreted using Kaplan-Meier plotter analysis and in vitro experiments, and this may help guide clinical therapeutic strategy and promote OS by individualizing therapy for GC patients.

SUBMITTER: Wu M

PROVIDER: S-EPMC7783202 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Prognostic Value of Autophagy-related Proteins in Human Gastric Cancer.

Wu Minmin M Chen Bicheng B Pan Xiaodong X Su Jiadong J

Cancer management and research 20201231

<h4>Purpose</h4>Autophagy-related proteins (ATG) play a crucial role in autophagy. Recently, the functions of autophagy in cancer have been gathering attention. However, the prognostic value of ATGs in gastric cancer (GC) has not been explored.<h4>Methods</h4>The Kaplan-Meier plotter (KM plotter) online database was used to examine the value of ATGs gene expression levels in overall survival (OS) prediction in GC patients with different clinical stage, differentiation, gender, HER2 status, and t ...[more]

PMID: 33414645

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Project description:BackgroundAutophagy is associated with cancer development. Autophagy-related genes play significant roles in endometrial cancer (EC), a major gynecological malignancy worldwide, but little was known about their value as prognostic markers. Here we evaluated the value of a prognostic signature based on autophagy-related genes for EC.MethodsFirst, various autophagy-related genes were obtained via the Human Autophagy Database and their expression profiles were downloaded from The Cancer Genome Atlas. Second, key prognostic autophagy-related genes were identified via univariate, LASSO and multivariate Cox regression analyses. Finally, a risk score to predict the prognosis of EC was calculated and validated by using the test and the entire data sets. Besides, the key genes mRNA expression were validated using quantitative real-time PCR in clinical tissue samples.ResultsA total of 40 differentially expressed autophagy-related genes in EC were screened and five of them were prognosis-related (CDKN1B, DLC1, EIF4EBP1, ERBB2 and GRID1). A prognostic signature was constructed based on these five genes using the train set, which stratified EC patients into high-risk and low-risk groups (p < 0.05). In terms of overall survival, the analyses of the test set and the entire set yielded consistent results (test set: p < 0.05; entire set: p < 0.05). Time-dependent ROC analysis suggested that the risk score predicted EC prognosis accurately and independently (0.674 at 1 year, 0.712 at 3 years and 0.659 at 5 years). A nomogram with clinical utility was built. Patients in the high-risk group displayed distinct mutation signatures compared with those in the low-risk group. For clinical sample validation, we found that EIF4EBP1and ERBB2 had higher level in EC than that in normal tissues while CDKN1B, DLC1 and GRID1 had lower level, which was consistent with the results predicted.ConclusionsBased on five autophagy-related genes (CDKN1B, DLC1, EIF4EBP1, ERBB2 and GRID1), our model can independently predict the OS of EC patients by combining molecular signature and clinical characteristics.

Project description:ObjectivesAutophagy plays a dual role in tumorigenesis. In the initial stages, it promotes cell survival and suppresses carcinogenesis, whereas in cancer development, it induces cancer cell survival. In this study, we investigate the role of autophagy as a protective or tumor suppressor mechanism in colorectal cancer (CRC) cell lines and evaluate its role as a potential biomarker in human tumor samples.Materials and methodsThe data of 68 patients with CRC treated at our Department from January 1 to December 31, 2016 were analyzed. Immunohistochemistry evaluation of p62, LC3B, Beclin-1, and Rab-7 in formalin-fixed paraffin-embedded tissue samples was performed and their expression was correlated with clinicopathologic characteristics, mutation status, and therapeutic approach. The χ was used to test an association among categorical variables. Survival curves were estimated using the Kaplan-Meier method and differences were assessed using the log-rank test. Colo-205, HT29, SW-480, and Caco-2 cell lines were also used so as to test the autophagy markers with oxaliplatin, irinotecan, hydroxychloroquine, and 3-methyladenine.ResultsOverexpression of Beclin-1 is associated with poor survival (P=0.001) in patients with CRC treated with chemotherapy, irrespective of the stage and mutational status. Rab-7 is also correlated with progression-free survival (PFS) (P=0.088). Oxaliplatin (10 and 20 μΜ) and irinotecan (10 and 20 μΜ) inhibit autophagy in microsatellite stable (MSS) CRC cell lines. The inhibition of autophagy in MSS CRC cell lines after treatment with oxaliplatin and irinotecan is further identified through monodancylcadaverine staining. Moreover, inhibition of autophagy with molecules such as hydroxychloroquine (20 μΜ) and 3-methyladenine (5 mM) was identified by the accumulation of p62 and LC3B.ConclusionsBeclin-1 is an independent prognostic factor of overall survival and PFS. Also, Rab-7 is identified as an independent prognostic factor of PFS. Besides, several chemotherapeutic drugs such as oxaliplatin and irinotecan inhibit autophagy in MSS CRC cell lines in a similar way like hydroxychloroquine and 3-methyladenine. Thus, in MSS patients who develop chemoresistance, a combination of other therapies that include an autophagy inhibitor could be more beneficial. Further clinical trials are needed to investigate these therapeutic strategies.

Dataset Information

Prognostic Value of Autophagy-related Proteins in Human Gastric Cancer.

Purpose

Methods

Results

Conclusion

Publications

Prognostic Value of Autophagy-related Proteins in Human Gastric Cancer.

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