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

Koustas, Evangelos; Sarantis, Panagiotis; Theoharis, Stamatios; Saetta, Angelica A.; Chatziandreou, Ilenia; Kyriakopoulou, Georgia; Giannopoulou, Ioanna; Michelli, Maria; Schizas, Dimitrios; Papavassiliou, Athanasios G.; Karamouzis, Michalis V.

doi:10.1097/coc.0000000000000592

Cited by 28 publications

(20 citation statements)

References 47 publications

(49 reference statements)

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“…e loss of autophagy-related protein Beclin-1 is associated with poor prognosis in CRC [22]. On the other hand, Koustas et al [23] showed that the overexpression of Beclin-1 indicated a poor prognosis in CRC patients receiving chemotherapy. e high expression of LC-3 is positively correlated with the long-term survival of patients with CRC, which could be used as a biomarker for its prognosis [24].…”

Section: Introductionmentioning

confidence: 99%

The Prognostic Value of Autophagy-Related Markers Bclin-1 and LC-3 in Colorectal Cancers: A Systematic Review and Meta-analysis

Yan

Liu

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Objective. At present, the relationship between autophagosomes and the prognosis of various cancers has become a subject of active investigation. A series of studies have demonstrated the correlation between autophagy microtubule-associated protein light chain 3 (LC-3), Beclin-1, and colorectal cancer (CRC). Since autophagy has dual regulatory roles in tumors, the results of this correlation are also uncertain. Hence, we summarized the relationship between Beclin-1, LC-3, and CRC using systematic reviews and meta-analysis to clarify their prognostic significance in it. Methods. PubMed, EMBASE, Cochrane Library, and Web of Science databases were searched online up to April 1, 2019. The quality of the involving studies was assessed against the Newcastle-Ottawa Scale (NOS). Pooled hazard ratio (HR) and 95% confidence interval (CI) in a fixed or random effects model were used to assess the strength of correlation between Beclin-1, LC-3, and CRC. Results. A total of 9 articles were collected, involving 2,297 patients. Most literatures scored more than 6 points, suggesting that the quality of our including research was acceptable. Our finding suggested that the expression of Beclin-1 was not associated with overall survival (HR = 0.68, 95% CI (0.31–1.52), P=0.351). Nonetheless, LC-3 expression exerted significant impact on OS (HR = 0.51, 95% CI (0.35–0.74), P<0.05). Subgroup analysis exhibited that Beclin-1 expression was associated with OS at TNM stage III (HR = 0.04, 95% CI = 0.02–0.08, P<0.05), surgical treatment (HR = 1.53, 95% CI (1.15–2.02), P=0.003), and comprehensive treatment (HR = 0.27 95% CI (0.08–0.92), P=0.036), respectively. Similarly, the results showed the increased LC-3 expression in CRC was related to OS in multivariate analyses (HR = 0.44, 95% CI (0.34–0.57), P<0.05), stages (HR = 0.51, 95% CI (0.35–0.74), P<0.05), and comprehensive treatment (HR = 0.44, 95% CI (0.34–0.57), P<0.05). Conclusions. Autophagy-related proteins of LC-3 might be an important marker of CRC progression. However, since the number of the original studies was limited, more well-designed, large-scale, high-quality studies are warranted to provide more convincing and reliable information.

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Section: Introductionmentioning

confidence: 99%

The Prognostic Value of Autophagy-Related Markers Bclin-1 and LC-3 in Colorectal Cancers: A Systematic Review and Meta-analysis

Yan

Liu

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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“…The role of autophagy in tumoral response is crucial in colorectal cancer. It has been shown in human colorectal tumors that surexpression of Beclin-1 was a poor prognosis factor with a lower efficacity of chemotherapy (37). Oxaliplatin inhibits autophagy in colorectal cancer with microsatellite stability (38).…”

Section: Discussionmentioning

confidence: 99%

A new Manganese superoxide dismutase mimetic improves oxaliplatin induced neuropathy and global tolerance on mice.

Prieux-Klotz

Bertrand

Chouzenoux

et al. 2022

Preprint

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Introduction: Reactive oxygen species (ROS) are produced by every aerobic cell during mitochondrial oxidative metabolism as well as in cellular response to xenobiotics, cytokines, and bacterial invasion. Oxidative stress is due to an imbalance between ROS or oxidants generation over the capability of the cell to elaborate an effective antioxidant response. Superoxide Dismutases (SOD) are antioxidant proteins that convert superoxide anion (O2•-) to hydrogen peroxide (H2O2). SOD mimetics can enhance the production of H2O2 and improve cytotoxic effect of chemotherapy. By using the differential in level of oxidative stress between normal and cancer cells, SOD mimetics can show an anti-tumoral effect and prevent oxaliplatin induced neuropathy. A new Pt(IV) conjugate prodrug called MAGOX, combining oxaliplatin and a Mn SOD mimic (MnSODm Mn1C1A) with a covalent link, was created. Methods In vitro, MAGOX anti-tumoral activity was assessed by the viability and ROS production of tumor cell lines (CT16, HCT 116, KC) and fibroblasts (primary culture and NIH 3T3) treated with Mn1C1A alone, conjugates (MAG2OX, MAGOX mono-OH, MAGOX mono-OAc), oxaliplatin and vehicle. In vivo, a murine model of colorectal cancer was created with subcutaneous injection of CT26 cells. After tumor growth, Balb/c mice underwent randomization in 4 groups: vehicle, oxaliplatin, MAG2OX and Mn1C1A. Tumor size and volume were measured weekly. Oxaliplatin induced peripheral neuropathy was assessed using a Von Frey test reflecting chronic hypoalgesia. Tolerance to treatment was assessed with a clinical score including 4 items: weight loss, weariness, alopecia and diarrhea. Results: In vitro, the MnSODm associated with oxaliplatin and MAG2OX treatment induced a significant higher production of H2O2 in all cell lines, by itself. In the group of cell lines treated with the association of Mn1C1A and oxaliplatin and the group treated with MAG2OX, a significant improvement of the anti-tumoral efficacy compared to oxaliplatin alone was observed. In vivo, the association of Mn1C1A to oxaliplatin did not decrease its anti-tumoral activity and MAG2OX had a lower anti-tumoral activity than oxaliplatin alone. Mn1C1A associated with oxaliplatin significantly decreased oxaliplatin induced peripheral neuropathy and also improved global clinical tolerance of oxaliplatin, therefore mice treated with Mn1C1A + oxaliplatin could receive more cumulated dose of oxaliplatin. Seric advanced oxidative protein products were higher in the Mn1C1A + oxaliplatin group versus oxaliplatin alone. PCR VEGF showed a higher VEGF RNA production in tumoral cells of mice treated with Mn1C1A than the other groups, as well as higher production of LC3 reflecting autophagy. Conclusion: A new Mn SOD mimetic called Mn1C1A associated with oxaliplatin showed superior anti tumoral activity than oxaliplatin, in vitro. The first Pt(IV) conjugate MAGOX had lower antitumoral activity, probably due to chemical instability issues. A new design is being evaluated. In vivo we observed a neuroprotective effect associated with a tolerance to oxaliplatin significantly improved, without impairing its antitumoral activity.

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“…[ 15 , 16 ] Meanwhile, autophagy-based prognostic markers for CRC have also been reported. [ 17 , 18 ] However, most studies only focus on autophagy without considering the heterogeneity of CRC. To our knowledge, no research has been done for risk stratification by integrating the autophagy system and the mesenchymal modalities of CMS4 in CRC.…”

Section: Discussionmentioning

confidence: 99%

“…We pooled and analyzed 6 public cohorts containing 1428 CRC patients to develop and validate an autophagy gene-based prognostic signature for CRC (APSCRC). Although autophagy prognostic markers for CRC have already been mentioned before, [ 17 , 18 ] risk assessment incorporating molecular subtypes has not been investigated. Our signature incorporates the autophagy system and tumor heterogeneity and would be useful for selecting patients with CRC to give more precise treatment.…”

Section: Introductionmentioning

confidence: 99%

Prognostic implications of an autophagy-based signature in colorectal cancer

et al. 2021

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Background: The heterogeneity of colorectal cancer (CRC) poses a significant challenge to the precise treatment of patients. CRC has been divided into 4 consensus molecular subtypes (CMSs) with distinct biological and clinical characteristics, of which CMS4 has the mesenchymal identity and the highest relapse rate. Autophagy plays a vital role in CRC development and therapeutic response. Methods: The gene expression profiles collected from 6 datasets were applied to this study. Network analysis was applied to integrate the subtype-specific molecular modalities and autophagy signature to establish an autophagy-based prognostic signature for CRC (APSCRC). Results: Network analysis revealed that 6 prognostic autophagy genes (VAMP7, DLC1, FKBP1B, PEA15, PEX14, and DNAJB1) predominantly regulated the mesenchymal modalities of CRC. The APSCRC was constructed by these 6 core genes and applied for risk calculation. Patients were divided into high- and low-risk groups based on APSCRC score in all cohorts. Patients within the high-risk group showed an unfavorable prognosis. In multivariate analysis, the APSCRC remained an independent predictor of prognosis. Moreover, the APSCRC achieved higher prognostic power than commercialized multigene signatures. Conclusions: We proposed and validated an autophagy-based signature, which is a promising prognostic biomarker of CRC patients. Further prospective studies are warranted to test and validate its efficiency for clinical application.

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

Abstract: Supplemental Digital Content is available in the text.

Cited by 28 publications

References 47 publications

The Prognostic Value of Autophagy-Related Markers Bclin-1 and LC-3 in Colorectal Cancers: A Systematic Review and Meta-analysis

The Prognostic Value of Autophagy-Related Markers Bclin-1 and LC-3 in Colorectal Cancers: A Systematic Review and Meta-analysis

A new Manganese superoxide dismutase mimetic improves oxaliplatin induced neuropathy and global tolerance on mice.

Prognostic implications of an autophagy-based signature in colorectal cancer

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