Light-Chain 3A Autophagic Activity and Prognostic Significance in Non-small Cell Lung Carcinomas

Karpathiou, Georgia; Sivridis, E.; Koukourakis, Michael I.; Mikroulis, Dimitrios; Bouros, Demosthenes; Froudarakis, Marios; Giatromanolaki, Alexandra

doi:10.1378/chest.10-1831

Cited by 76 publications

(66 citation statements)

References 29 publications

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“…Importantly, some of these abnormalities have been shown to correlate with clinicopathological parameters and disease outcomes including overall survival in cancer patients. These findings not only underscore a pivotal role of autophagy in tumorigenesis, but also highlight the possibility of using autophagy-associated molecules as novel prognostic markers in clinical settings (Russell et al, 1990;Eccles et al, 1992;Futreal et al, 1992;Cliby et al, 1993;Saito et al, 1993;Gao et al, 1995;Ahn et al, 2007;Miracco et al, 2007Miracco et al, , 2010Ding et al, 2008;Fujii et al, 2008;Yoshioka et al, 2008;Kim et al, 2008a;Kang et al, 2009;Lazova and Pawelek, 2009;Nomura et al, 2009;Othman et al, 2009;Pirtoli et al, 2009;Li et al, 2009Zhang et al, 2009a;Koukourakis et al, 2010;Lazova et al, 2010;Miao et al, 2010;Negri et al, 2010;Sivridis et al, 2010;Wan et al, 2010;Karpathiou et al, 2010;Chang et al, 2011;Ma et al, 2011).…”

Section: Dysregulation Of Autophagy In Human Cancersmentioning

confidence: 88%

The autophagic paradox in cancer therapy

et al. 2011

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Autophagy, hallmarked by the formation of doublemembrane bound organelles known as autophagosomes, is a lysosome-dependent pathway for protein degradation. The role of autophagy in carcinogenesis is context dependent. As a tumor-suppressing mechanism in earlystage carcinogenesis, autophagy inhibits inflammation and promotes genomic stability. Moreover, disruption of autophagy-related genes accelerates tumorigenesis in animals. However, autophagy may also act as a prosurvival mechanism to protect cancer cells from various forms of cellular stress. In cancer therapy, adaptive autophagy in cancer cells sustains tumor growth and survival in face of the toxicity of cancer therapy. To this end, inhibition of autophagy may sensitize cancer cells to chemotherapeutic agents and ionizing radiation. Nevertheless, in certain circumstances, autophagy mediates the therapeutic effects of some anticancer agents. Data from recent studies are beginning to unveil the apparently paradoxical nature of autophagy as a cellfate decision machinery. Taken together, modulation of autophagy is a novel approach for enhancing the efficacy of existing cancer therapy, but its Janus-faced nature may complicate the clinical development of autophagy modulators as anticancer therapeutics.

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Section: Dysregulation Of Autophagy In Human Cancersmentioning

confidence: 88%

The autophagic paradox in cancer therapy

et al. 2011

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“…In this study, we found that LC3Av1 was frequently inactivated at the transcriptional level in various human cancer cell lines and at least some primary ESCCs, and its inactivation was due to epigenetic changes through aberrant DNA methylation. However, a recent immunohistochemical analysis in tumor tissues revealed a 'stone-like' staining pattern of LC3A to be associated with a poor prognosis among patients with epithelial tumors, including colorectal adenocarcinoma, non-small cell lung carcinoma, and breast tumors (Giatromanolaki et al, 2010;Karpathiou et al, 2010;Sivridis et al, 2010aSivridis et al, , 2010bSivridis et al, , 2011. However, the specificity of the LC3A antibody used was not examined, though LC3Av1 and LC3B are highly homologous in amino-acid sequence.…”

Section: Discussionmentioning

confidence: 99%

A transcriptional variant of the LC3A gene is involved in autophagy and frequently inactivated in human cancers

et al. 2012

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Microtubule-associated protein 1 light chain 3 has an important role in autophagy. The human LC3 gene family has five members, LC3A (variant-1: v1 and -2: v2), LC3B, LC3B2 and LC3C. Although a form of LC3B modified by phosphatidylethanolamine (form-II) is localized in autophagosomes, it is not clear whether other LC3 proteins also function in autophagy. Here, we examined the association between autophagy and human LC3 proteins during starvation-or p53-induced autophagy in Saos-2 cells. In an analysis of the intracellular distribution of each LC3 protein fused with GFP, GFP-LC3Av1 was frequently localized in autophagosomes with a punctate pattern, similar to GFP-LC3B. Further, endogenous LC3Av1 generated form-II and mostly localized in LC3B-positive autophagosomes during the induced autophagy. Interestingly, LC3Av1, not LC3B, was frequently inactivated at the transcriptional level in various human cancer cell lines (111/244 cell lines, 45.5%) and its inactivation was due to aberrant DNA methylation in esophageal squamous cell carcinoma (ESCC) cell lines and primary tumors. Restoration of LC3Av1 expression in KYSE170 cells, an LC3Av1-inactivated ESCC cell line, showed the inhibition of tumor growth in vivo. These results suggest that LC3Av1, not only LC3B, functions in autophagy and further, LC3Av1 may be crucial in carcinogenesis.

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“…LC3A is a key mediator of autophagy and specific studies have indicated that the immunohistochemical determination of LC3A expression is a useful prognostic indicator (15)(16)(17). Fujii et al (27) demonstrated that high LC3A expression correlates with reduced disease-free and overall patient survival.…”

Section: A B C Dmentioning

confidence: 99%

“…Fujii et al (27) demonstrated that high LC3A expression correlates with reduced disease-free and overall patient survival. In addition, more recent studies have found that LC3A exhibits three expression patterns in numerous human malignancies; diffuse cytoplasmic, cytoplasmic/juxtanuclear and SLS (14)(15)(16)(17)(18). High numbers of SLS have been linked to poor patient outcome, whereas the remaining two expression patterns have demonstrated no prognostic significance.…”

Section: A B C Dmentioning

confidence: 99%

“…Using the immunohistochemical detection of LC3A protein as a marker of autophagic activity, autophagy was identified to be upregulated in urothelial cell carcinoma, non-small cell lung cancer and endometrial, colorectal and cutaneous squamous cell carcinomas (14)(15)(16)(17)(18). In addition, LC3A overexpression is linked to the aggressiveness of these tumors (16).…”

Section: Introductionmentioning

confidence: 99%

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High p53 and MAP1 light chain 3A co-expression predicts poor prognosis in patients with esophageal squamous cell carcinoma

Wang

Xian-zhong

Chen

et al. 2013

Molecular Medicine Reports

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Abstract. p53 and microtubule-associated protein 1 light chain 3A (LC3A) are regulators of apoptosis and autophagy and are expressed at high levels in a number of human tumors. The purpose of the current study was to evaluate the clinicopathological and prognostic significance of p53 and LC3A expression levels in esophageal squamous cell carcinomas (ESCCs). p53 and LC3A expression levels were measured by immunohistochemistry in 114 patients with stage II/III (T any N+M 0 or T 3,4 N any M 0 ) ESCCs treated with surgery followed by adjuvant concurrent chemoradiotherapy. The overexpression of p53 and LC3A was observed in 57 and 54% of ESCC samples, respectively. p53 staining was nuclear and LC3A was localized to the cytoplasm of tumor cells. p53 overexpression was more frequently observed in ESCCs with positive lymph nodes (P=0.017). Patients with ESCCs overexpressing p53 and LC3A were associated with a lower 5-year overall survival rate than those with low p53 and LC3A expression (18.0 vs. 54.4%; P=0.001). Univariate and multivariate analyses revealed that the overexpression of p53 or LC3A was not associated with poor patient outcome (P>0.05). However, patients with high levels of p53 and LC3A co-expression had poor clinical prognoses (P=0.027). Thus, p53 and LC3A co-expression is an independent prognostic marker for patients with ESCC. IntroductionEsophageal carcinoma (EC) is a public health issue in China (1). It has a poor overall prognosis and treatment outcomes for patients with EC have not improved over the last few decades. Significant prognostic indicators include the extent of invasion and lymph node and distal metastases (2). However, specific patients with the same stage have different prognosis (3). Therefore, molecular markers to improve the outcome prediction for patients with EC must be identified.Classified as type I programed cell death, apoptosis is involved in a number of cancer-related processes, including tumorigenesis, tumor progression and cellular responses to chemotherapy and radiotherapy (4-6). The well-studied tumor suppressor protein, p53, is key to apoptosis and cancer development. Wild-type p53 inhibits tumor growth by inducing apoptosis and inhibiting angiogenesis and metastasis; however, the TP53 gene undergoes inactivating mutations in a variety of cancer types. More recently, p53 has been demonstrated to repress autophagy (7), indicating that apoptosis and autophagy may interact. Type II programmed cell death, or autophagy, is an evolutionarily conserved eukaryotic process important for maintaining homeostasis by recycling stable proteins and long-lived organelles (8).Autophagy is important in a number of physiological processes, including adaptation to hypoxia, prevention of tumorigenesis and antigen presentation (9-11). Although the role of autophagy in cancer is unclear, the current view is that it functions as a cytoprotective mechanism during tumor progression (12).Previously, microtubule-associated protein 1 light chain 3A (LC3A), one of three microtubule-associated protein ...

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Light-Chain 3A Autophagic Activity and Prognostic Significance in Non-small Cell Lung Carcinomas

Cited by 76 publications

References 29 publications

The autophagic paradox in cancer therapy

The autophagic paradox in cancer therapy

A transcriptional variant of the LC3A gene is involved in autophagy and frequently inactivated in human cancers

High p53 and MAP1 light chain 3A co-expression predicts poor prognosis in patients with esophageal squamous cell carcinoma

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