Autophagy in endometrial carcinomas and prognostic relevance of 'stone-like' structures (SLS): What is destined for the atypical endometrial hyperplasia?

Sivridis, Efthimios; Giatromanolaki, Alexandra; Liberis, V.; Koukourakis, Michael I.

doi:10.4161/auto.7.1.13947

Cited by 53 publications

(56 citation statements)

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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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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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“…In contrast, more aggressive type II serous tumors showed a dramatic mRNA increase of an autophagy inducer, CDKN2A ( Table 2; Table S5), previously reported to distinguish serous from endometrioid carcinomas by high protein expression 13,44 and to be associated with migration and invasion. 45 Both protein products of CDKN2A (ARF and INK4a) induce autophagy 46,47 and a recent IHC analysis of 360 UCEC patient samples shows higher counts of MAP1LC3A/LC3A 'stone-like structures' that are associated with poor prognosis subtypes, 48 including: serous papillary, clear cell, and high-grade endometrioid. Further study of the autophagy status of less aggressive type I endometrioid tumors compared to more aggressive type II serous tumors may reveal a role for autophagy in the pathogenesis of endometrial carcinomas.…”

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confidence: 99%

Cross-cancer profiling of molecular alterations within the human autophagy interaction network

et al. 2015

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Aberrant activation or disruption of autophagy promotes tumorigenesis in various preclinical models of cancer, but whether the autophagy pathway is a target for recurrent molecular alteration in human cancer patient samples is unknown. To address this outstanding question, we surveyed 211 human autophagy-associated genes for tumorrelated alterations to DNA sequence and RNA expression levels and examined their association with patient survival outcomes in multiple cancer types with sequence data from The Cancer Genome Atlas consortium. We found 3 (RB1CC1/FIP200, ULK4, WDR45/WIPI4) and one (ATG7) core autophagy genes to be under positive selection for somatic mutations in endometrial carcinoma and clear cell renal carcinoma, respectively, while 29 autophagy regulators and pathway interactors, including previously identified KEAP1, NFE2L2, and MTOR, were significantly mutated in 6 of the 11 cancer types examined. Gene expression analyses revealed that GABARAPL1 and MAP1LC3C/LC3C transcripts were less abundant in breast cancer and non-small cell lung cancers than in matched normal tissue controls; ATG4D transcripts were increased in lung squamous cell carcinoma, as were ATG16L2 transcripts in kidney cancer. Unsupervised clustering of autophagy-associated mRNA levels in tumors stratified patient overall survival in 3 of 9 cancer types (acute myeloid leukemia, clear cell renal carcinoma, and head and neck cancer). These analyses provide the first comprehensive resource of recurrently altered autophagy-associated genes in human tumors, and highlight cancer types and subtypes where perturbed autophagy may be relevant to patient overall survival.

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“…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%

“…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%

“…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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Autophagy in endometrial carcinomas and prognostic relevance of 'stone-like' structures (SLS): What is destined for the atypical endometrial hyperplasia?

Cited by 53 publications

References 51 publications

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

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

Cross-cancer profiling of molecular alterations within the human autophagy interaction network

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

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