Autophagy-related Proteins as a Prognostic Factor of Patients With Colorectal Cancer

Autor: Panagiotis Sarantis, Maria Michelli, Dimitrios Schizas, Michalis V. Karamouzis, Stamatios Theoharis, Georgia Kyriakopoulou, Athanasios G. Papavassiliou, Ioanna Giannopoulou, Ilenia Chatziandreou, Evangelos Koustas, Angelica A. Saetta
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Male
Cancer Research
Colorectal cancer
Autophagy-Related Proteins
Kaplan-Meier Estimate
medicine.disease_cause
chemotherapy
Cohort Studies
0302 clinical medicine
030212 general & internal medicine
Aged
80 and over
Biopsy
Needle
Middle Aged
Original Articles: Gastrointestinal
Prognosis
Combined Modality Therapy
Immunohistochemistry
3. Good health
Oncology
030220 oncology & carcinogenesis
ComputingMethodologies_DOCUMENTANDTEXTPROCESSING
Beclin-1
Female
Colorectal Neoplasms
medicine.drug
Adult
autophagy
colorectal cancer
Disease-Free Survival
Statistics
Nonparametric
03 medical and health sciences
Cell Line
Tumor
medicine
Biomarkers
Tumor
Humans
neoplasms
Survival analysis
Aged
Retrospective Studies
business.industry
Autophagy
Hydroxychloroquine
medicine.disease
Survival Analysis
digestive system diseases
Oxaliplatin
Irinotecan
Cancer cell
Mutation
Cancer research
Carcinogenesis
business
Zdroj: American Journal of Clinical Oncology
ISSN: 1537-453X
0277-3732
Popis: Supplemental Digital Content is available in the text.
Objectives: Autophagy 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 Methods: The 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 χ2 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. Results: Overexpression 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. Conclusions: Beclin-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.
Databáze: OpenAIRE
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