Overexpression and altered subcellular localization of autophagy-related 16-like 1 in human oral squamous-cell carcinoma: correlation with lymphovascular invasion and lymph-node metastasis

Nomura, Hitomi; Uzawa, Katsuhiro; Yamano, Y.; Fushimi, Kazuaki; Ishigami, Takashi; Kouzu, Yukinao; Koike, Hirofumi; Siiba, Masashi; Bukawa, Hiroki; Yokoe, Hidetaka; Kubosawa, Hitoshi; Tanzawa, Hideki

doi:10.1016/j.humpath.2008.06.018

Cited by 32 publications

(26 citation statements)

References 33 publications

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“…5). These results are consistent with previous biomarker studies showing that increased expression of autophagy markers, such as ATG16L, in the tumor stroma is specifically associated with metastatic tumor progression and/or poor clinical outcome (82).…”

Section: Caveolin-1 and Cafssupporting

confidence: 93%

Warburg Meets Autophagy: Cancer-Associated Fibroblasts Accelerate Tumor Growth and MetastasisviaOxidative Stress, Mitophagy, and Aerobic Glycolysis

Pavlides

Vera

Gândara

et al. 2012

Antioxidants & Redox Signaling

262

207

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Significance: Here, we review certain recent advances in oxidative stress and tumor metabolism, which are related to understanding the contributions of the microenvironment in promoting tumor growth and metastasis. In the early 1920s, Otto Warburg, a Nobel Laureate, formulated a hypothesis to explain the ''fundamental basis'' of cancer, based on his observations that tumors displayed a metabolic shift toward glycolysis. In 1963, Christian de Duve, another Nobel Laureate, first coined the phrase auto-phagy, derived from the Greek words ''auto'' and ''phagy,'' meaning ''self'' and ''eating.'' Recent Advances: Now, we see that these two ideas (autophagy and aerobic glycolysis) physically converge in the tumor stroma. First, cancer cells secrete hydrogen peroxide. Then, as a consequence, oxidative stress in cancer-associated fibroblasts drives autophagy, mitophagy, and aerobic glycolysis. Critical Issues: This ''parasitic'' metabolic coupling converts the stroma into a ''factory'' for the local production of recycled and high-energy nutrients (such as L-lactate)-to fuel oxidative mitochondrial metabolism in cancer cells. We believe that Warburg and de Duve would be pleased with this new two-compartment model for understanding tumor metabolism. It adds a novel stromal twist to two very well-established cancer paradigms: aerobic glycolysis and autophagy. Future Directions: Undoubtedly, these new metabolic models will foster the development of novel biomarkers, and corresponding therapies, to achieve the goal of personalized cancer medicine. Given the central role that oxidative stress plays in this process, new powerful antioxidants should be developed in the fight against cancer. Antioxid. Redox Signal. 16, 1264-1284.Breast Cancer-General Knowledge C ancer is a multifactorial disease caused by the combination of environmental, genetic, and behavioral factors. It is characterized by uncontrollable cell division, a change in cell morphology, and the ability of the cancer cell to develop an invasive phenotype.Breast cancer is one of the major causes of cancer mortality in women. The incidence of breast cancer is still increasing worldwide. It is estimated that in the year 2011, there will be about 200,000 new cases of invasive breast cancer in the United States alone. These data translate to 1 in 8 (*12%) women developing some form of breast cancer, over the course of their lifetime. About 5-10% of breast cancer cases are due to familial/inherited mutations within the BRCA1 or BRCA2 genes. Further, about 20-30% of women diagnosed with breast cancer have a family history of cancer. However, the most important risk factor for breast cancer is increased age (over 45 years old). Other risk factors can be prevented or modified, such as hormone use, low physical activity, alcohol consumption, diet, obesity, and smoking (2).Breast cancer, like most cancers, is highly variable with great clinical heterogeneity. Gene profiling and highthroughput expression technologies have prompted the

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Section: Caveolin-1 and Cafssupporting

confidence: 93%

Warburg Meets Autophagy: Cancer-Associated Fibroblasts Accelerate Tumor Growth and MetastasisviaOxidative Stress, Mitophagy, and Aerobic Glycolysis

Pavlides

Vera

Gândara

et al. 2012

Antioxidants & Redox Signaling

262

207

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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: 89%

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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“…The slides were then lightly counterstained with hematoxylin, dehydrated with ethanol, cleaned with xylene and mounted. To quantify the state of FHL1 protein expression in those components, we used IHC score systems described previously (18,(22)(23)(24)(25)(26)(27)(28)(29)(30). Briefly, the stained cells were determined in at least five random fields at magnification x400 in each section.…”

Section: Methodsmentioning

confidence: 99%

High prevalence of epigenetic inactivation of the human four and a half LIM domains 1 gene in human oral cancer

Koike

Kasamatsu

Iyoda

et al. 2012

International Journal of Oncology

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Abstract.The four and a half LIM domains 1 (FHL1) gene has been related to carcinogenesis. However, the expression status of FHL1 in human oral squamous cell carcinoma (OSCC) remains unclear and the detailed mechanism of gene silencing is poorly understood. The aim of this study was to examine the FHL1 expression level and its regulatory mechanism in OSCCs. Quantitative reverse-transcriptase-polymerase chain reaction (PCR) and western blotting showed significant downregulation of FHL1 in all OSCC-derived cell lines (Sa3, HSC-2, HSC-3, HSC-4, HO-1-u-1, HO-1-N-1, KON and Ca9-22) compared to human normal oral keratinocytes. We also found that FHL1 mRNA expression was frequently downregulated (P<0.01) in 51 (86.4%) of 59 primary OSCCs compared with the corresponding normal oral tissues, while there was no significant difference between the status of the FHL1 protein expression in OSCCs and the clinicopathological features. Using methylationspecific PCR, we detected methylated FHL1 in all cell lines and treatment with the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine restored the FHL1 expression. However, no significant restoration of FHL1 expression was observed using sodium butyrate, an inhibitor of histone deacetylase and chromatin immunoprecipitation showed that histone H3 lysine 9 in the FHL1 promoter region was significantly acetylated. In addition, no mutation in the entire coding region of the FHL1 gene was found. Therefore, our data suggested that inactivation of the FHL1 gene is a frequent event during oral carcinogenesis and that the mechanism of FHL1 downregulation in OSCCs is through DNA methylation of the promoter region rather than histone deacetylation or mutation. IntroductionHead and neck squamous cell carcinoma (HNSCC) is one of the most frequently occurring malignancies and a major cause of morbidity and mortality (1,2). Oral cancer is the most common among the HNSCCs and the most frequently occurring oral cancer is squamous cell carcinoma (OSCC), which accounts for more than 90% of all oral malignancies (3). The number of OSCC cases that occur worldwide annually exceeds 300,000 (4). The mechanisms behind tumor progression of OSCC are known to a limited extent, indicating a clear need for comprehensive knowledge that can lead to more specific and effective molecular target.Microarray technology facilitates simultaneous evaluation of thousands of genes in a specimen. The results of microarray analysis provide researchers with high throughput screening to study the roles played by specific genes in cancer development and progression. We previously reported gene expression profiling of OSCC to identify cancer-related genes (5,6).The four and a half LIM domains (FHL) family of genes is characterized by LIM domains, a term derived from the first letters of three transcription factors: Lin-11, Isl-1 and Mec-3. Because the LIM domains provide protein-protein binding interfaces, the FHL genes play an important role in cellular events such as focal adhesion and differentiation by repressing or ac...

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Overexpression and altered subcellular localization of autophagy-related 16-like 1 in human oral squamous-cell carcinoma: correlation with lymphovascular invasion and lymph-node metastasis

Cited by 32 publications

References 33 publications

Warburg Meets Autophagy: Cancer-Associated Fibroblasts Accelerate Tumor Growth and MetastasisviaOxidative Stress, Mitophagy, and Aerobic Glycolysis

Warburg Meets Autophagy: Cancer-Associated Fibroblasts Accelerate Tumor Growth and MetastasisviaOxidative Stress, Mitophagy, and Aerobic Glycolysis

The autophagic paradox in cancer therapy

High prevalence of epigenetic inactivation of the human four and a half LIM domains 1 gene in human oral cancer

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