Distinct expression patterns and roles of aldehyde dehydrogenases in normal oral mucosa keratinocytes: differential inhibitory effects of a pharmacological inhibitor and RNAi-mediated knockdown on cellular phenotype and epithelial morphology

Kato, Hiroko; Izumi, Kenji; Saito, Taro; Ohnuki, Hisashi; Terada, Makoto; Kawano, Yoshiro; Nozawa-Inoue, Kayoko; Saito, Chikara; Maeda, Takeyasu

doi:10.1007/s00418-012-1064-7

Cited by 20 publications

(19 citation statements)

References 45 publications

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“…All individuals signed informed consent before the tissue samples were procured. Primary human oral keratinocytes were isolated and cultured routinely in a “complete” EpiLife® (Life Technologies, Carlsbad, CA) supplemented with EpiLife® Defined Growth Supplements (Life Technologies), 0.06 mM Ca ++ , Gentamicin (5.0 μg/mL; Life Technologies), and Amphotericin B (0.375 μg/mL; Life Technologies) as described previously (Kato et al, 2013). The majority of cells used in this study were from 4th to 7th passage, inclusive.…”

Section: Methodsmentioning

confidence: 99%

Hypoxia Induces an Undifferentiated Phenotype of Oral Keratinocytes in vitro

Kato

Izumi

Uenoyama

et al. 2014

Cells Tissues Organs

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The aim of this study was to determine the effects of hypoxia on the proliferating potential and phenotype of primary human oral keratinocytes cultured at ambient oxygen tension (20%) or at different levels of hypoxia (2 and 0.5% O₂). The effects of oxygen tensions on cellular metabolic activity, cell proliferation, clonogenicity and proliferation heterogeneity were measured. Cell cycle profiles were analyzed by a fluorescent-activated cell sorter, and p21^WAF1/CIP1 expression in the G₀/G₁ phase was also concomitantly quantitated. The expression levels of cell cycle regulatory proteins were examined by immunoblotting, and the cellular senescence was assessed by senescence-associated β-galactosidase staining. Basal and suprabasal keratinocyte phenotypes were determined by the expression levels of 14-3-3σ, p75^NTR and α6 integrin. Despite having a lower metabolism, the proliferation rate and clonogenic potential were remarkably enhanced in hypoxic cells. The significantly higher percentage of cells in the G₀/G₁ phase under hypoxia and the expression patterns of cell cycle regulatory proteins in hypoxic cells were indicative of a state of cell cycle arrest in hypoxia. Furthermore, a decrease in the expression of p21^WAF1/CIP1 and p16^INK4A and fewer β-galactosidase-positive cells suggested a quiescent phenotype rather than a senescent one in hypoxic cells. Compared with normoxic cells, the differential expression patterns of keratinocyte phenotypic markers suggest that hypoxic cells that generate minimal reactive oxygen species, suppress the mammalian target of rapamycin activity and express hypoxia-inducible factor-1α favor a basal cell phenotype. Thus, regardless of the predisposition to the state of cell cycle arrest, hypoxic conditions can maintain oral keratinocytes in vitro in an undifferentiated and quiescent state.

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Section: Methodsmentioning

confidence: 99%

Hypoxia Induces an Undifferentiated Phenotype of Oral Keratinocytes in vitro

Kato

Izumi

Uenoyama

et al. 2014

Cells Tissues Organs

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“…ALDH1A1 is not expressed in the normal oral mucosa (14,15). However, other ALDH isoenzymes, such as ALDH1A3 and ALDH3A1, are found (14).…”

Section: Discussionmentioning

confidence: 99%

Expression of ALDH1A1 and CD44 in primary head and neck squamous cell carcinoma and their value for carcinogenesis, tumor progression and cancer stem cell identification

et al. 2015

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Abstract. In head and neck squamous cell carcinoma (HNSCC), aldehyde dehydrogenase 1 family, member A1 (ALDH1A1) and hyaluronan receptor cluster of differentiation 44 (CD44) are often used as cancer stem cell (CSC) markers. The aim of the present study was to examine the relevance of these proteins for HNSCC in general and for the identification of CSCs. Tumors from 48 patients with primary HNSCC were analyzed for the expression of ALDH1A1 and CD44. Additionally, the association of the proteins with the proliferation rate and epidermal growth factor receptor (EGFR) expression was analyzed. ALDH1A1 was expressed in 54.2% of the carcinoma samples while CD44 was expressed in 89.6% of the carcinoma samples. Most notably, these proteins were often not expressed exclusively in a subpopulation, but also in the majority of tumor cells (ALDH1A1: 30.8% of ALDH1A1 + tumors; CD44: 65.1% of CD44 + tumors). Furthermore, patients with ALDH1A1 + tumors exhibited worse survival rates. CD44 and EGFR expression patterns were overlapping within the tumors and the expression rates were significantly connected. Ki-67 + tumor cells often expressed CD44. ALDH1A1 and CD44 expression patterns only partly overlapped. Consequently, ALDH1A1 and CD44 play significant roles in carcinogenesis and tumor progression. Within the present study, CD44 appeared to interact with EGFR and was more often expressed in primary HNSCC than the marker ALDH1A1. However, ALDH1A1 was a better marker to define a subpopulation of tumor cells. Finally, neither ALDH1A1 nor CD44, alone or combined, were sufficient to determine the CSC population in HNSCC.

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“…Genetic variants of these enzymes result in their low activity and decrease the clearance of ethanol and acetaldehyde from tissues. ALDH2 polymorphism, typically observable in East Asian subjects, correlates to high levels of acetaldehyde, in turn related to high risk of oral cancer [ 51 , 52 , 53 ]. In addition, endogenous salivary ADH is not the only responsible for the acetaldehyde production in the oral cavity: bacterial ADHs contribute to raise the salivary acetaldehyde levels and, consequently, may contribute to the epithelial cell proliferation [ 54 , 55 ] and DNA adduct formation [ 56 ].…”

Section: Beneficial and Harmful Components Of Winementioning

confidence: 99%

Ethanol versus Phytochemicals in Wine: Oral Cancer Risk in a Light Drinking Perspective

Varoni

Lodi

2015

IJMS

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This narrative review aims to summarize the current controversy on the balance between ethanol and phytochemicals in wine, focusing on light drinking and oral cancer. Extensive literature search included PUBMED and EMBASE databases to identify in human studies and systematic reviews (up to March 2015), which contributed to elucidate this issue. Independently from the type of beverage, meta-analyses considering light drinking (≤1 drinks/day or ≤12.5 g/day of ethanol) reported relative risks (RR) for oral, oro-pharyngeal, or upper aero-digestive tract cancers, ranging from 1.0 to 1.3. One meta-analysis measured the overall wine-specific RR, which corresponded to 2.1. Although little evidence exists on light wine intake, phytochemicals seem not to affect oral cancer risk, being probably present below the effective dosages and/or due to their low bioavailability. As expected, the risk of oral cancer, even in light drinking conditions, increases when associated with smoking habit and high-risk genotypes of alcohol and aldehyde dehydrogenases.

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Distinct expression patterns and roles of aldehyde dehydrogenases in normal oral mucosa keratinocytes: differential inhibitory effects of a pharmacological inhibitor and RNAi-mediated knockdown on cellular phenotype and epithelial morphology

Cited by 20 publications

References 45 publications

Hypoxia Induces an Undifferentiated Phenotype of Oral Keratinocytes in vitro

Hypoxia Induces an Undifferentiated Phenotype of Oral Keratinocytes in vitro

Expression of ALDH1A1 and CD44 in primary head and neck squamous cell carcinoma and their value for carcinogenesis, tumor progression and cancer stem cell identification

Ethanol versus Phytochemicals in Wine: Oral Cancer Risk in a Light Drinking Perspective

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