Aldehyde dehydrogenase 1B1 (ALDH1B1) is a potential biomarker for human colon cancer.

알데하이드 디하이드로제나아제 1B1 (ALDH1B1)은 사람 대장암을 위한 잠재적 마커이다.

AHDHs는 NAD(P)+ 의존 효소 슈퍼페밀리에 속하며 내인성과 외인성 알데하이드들의 산화를 촉진시킨다. 부분적으로 ALDH1A1, ALDHs의 증가된 활성/발현은 사람 암의 생성에 대해 보고되었다. 

ALDH1A1의 대사적 기능은 정상/암줄기세포에 줄기세포 특성을 부여한다고 제안하고 있다. 그럼에도 불구하고, 특정 타입의 사람 암에서의 증가된 ALDH 활성에 대한 ALDH isozymes의 확인은 여전히 설명되지 않았다. ALDH1B1은 미토콘드리아의 ALDH로, 넓은 범위의 아세트알데하이드를 포함한 알데하이드 기질들과 지질과산화(lipid peroxidation-LPO) 생산물을 대사작용 시킨다.

이 논문에서는 NIH tissue array를 이용하여 대장, 폐, 유방, 난소의 아데노카시노마에서의 ALDH1A1과 ALDH1B1의 발현 정도를 확인하였다. 종양 조직에서의 면역조직 화학상의 ALDH1A1 또는 ALDH1B1의 발현은 강도(scale=1~3)와 범위(총 암 세포의 %)로 수치화하였다. 여기서 ALDH1A1보다 ALDH1B1가 암 조직에서 5.6배 더 높이 발현되는 것을 보고하였다. 두드러지게 40개의 대장암 샘플 중 39개에서 ALDH1B1 염색에 대해 양성으로 판명되었다. 이 연구는 ALDH1B1이 ALDH1A1에 비해 더 많이 발현되며 ALDH1B1이 궁극적으로 사람 대장 아데노카시노마에서 업레규레이트 되면서 사람 대장암을 위한 잠재적 마커로 사용될 수 있다. 

 

 

 

Aldehyde dehydrogenases (ALDHs) belong to a superfamily of NAD(P)(+)-dependent enzymes, which catalyze the oxidation of endogenous and exogenous aldehydes to their corresponding acids. Increased expression and/or activity of ALDHs, particularly ALDH1A1, have been reported to occur in human cancers.

It is proposed that the metabolic function of ALDH1A1 confers the stemness properties to normal and cancer stem cells. Nevertheless, the identity of ALDH isozymes that contribute to the enhanced ALDH activity in specific types of human cancers remains to be elucidated. ALDH1B1 is a mitochondrial ALDH that metabolizes a wide range of aldehyde substrates including acetaldehyde and products of lipid peroxidation (LPO).  

In this study, we immunohistochemically examined the expression profile of ALDH1A1 and ALDH1B1 in human adenocarcinomas of colon (N=40), lung (N=30), breast (N=33) and ovary (N=33) using an NIH tissue array. The immunohistochemical expression of ALDH1A1 or ALDH1B1 in tumor tissues was scored by their intensity (scale=1-3) and extensiveness (% of total cancer cells). Herein we report a 5.6-fold higher expression score for ALDH1B1 in cancerous tissues than that for ALDH1A1. Remarkably, 39 out of 40 colonic cancer specimens were positive for ALDH1B1 with a staining intensity of 2.8~0.5. Our study demonstrates that ALDH1B1 is more profoundly expressed in the adenocarcinomas examined in this study relative to ALDH1A1 and that ALDH1B1 is dramatically upregulated in human colonic adenocarcinoma, making it a potential biomarker for human colon cancer.

Reference:

Chen Y, Orlicky DJ, Matsumoto A, Singh S, Thompson DC, Vasiliou V.
Biochem Biophys Res Commun. 2011 Feb 11;405(2):173-9.

PMID: 
21216231

 

 

 

 

 

 

 

 

The ALDH1A1 gene product is a cytosolic homo-tetramer (~55 kDa subunits) expressed in a number of tissues including brain, cornea, lens, retina, liver, and gastrointestinal tract (9723161) (11744377) (9973596) . ALDH1A1 is one of four known vertebrate retinaldehyde dehydrogenases and is often referred to in the literature as RALDH1 (1292933) retaining a high affinity for all-trans and 9-cis-retinaldehyde (Km < 0.1 umol/L) and acetaldehyde (Km ~ 50-100 umol/L) (1292933) .

The retinaldehyde dehydrogenases play a significant role in vertebrate embryogenesis. Retinoic acid (RA) is a low molecular weight (300 Da), lipophilic, rapidly-diffusing signaling molecule essential for growth and developmental processes in the embryo. It is produced in vivo via a two-step enzymatic pathway oxidizing retinols such as vitamin A (all-trans-retinol) by specific cytosolic alcohol or microsomal retinol dehydrogenases to retinaldehyde and then to retinoic acid by one of several cytosolic retinaldehyde dehydrogenases. ALDH1A1 was first shown to catalyze the irreversible oxidation of retinaldehyde to its carboxylic acid, retinoic acid (10880953) . Studies have been conducted to address the role of ALDH1A1 genes during organogenesis and embryonic development using transgenic and knockout animals (11744377) . These studies have shown that the pups are viable and may demonstrate redundancies in retinoic acid synthesis during development.

ALDH1A1\'s abundant expression in the mammalian cornea and lens categorizes it as a corneal crystalline based on the similarity in the level of expression to lens enzyme crystallins (9695791) (9599288) . Although the exact function of this enzyme in the cornea and lens remains a matter of controversy there is evidence that it may play a role in the development and/or maintenance of tissue transparency through its affects on light-scattering and absorption (9973596) as well as a metabolic role in mitigating the effects of oxidative stress (12941160) .

ALDH1A1 has been linked to drug resistance against oxazaphosphorines, including cyclophosphamide in various tumor types (7484368) (8124665) . Its over-expression in a number of cell lines and normal hematopoietic progenitor cells results in a significant increase in resistance to the active metabolites of cyclophosphamide (10773007) .

ALDH1A1 has been implicated in several alcohol-related phenotypes including alcoholism, alcohol-induced flushing and alcohol sensitivity. Acetaldehyde formed during ethanol metabolism is efficiently metabolized by ALDH1A1 to non-toxic metabolites. Due to the role of ALDH1A1 in acetaldehyde metabolism, ALDH1A1 inhibition by the anti-alcoholic medication, disulfiram (>90%) or low ALDH1A1 activity due to polymorphisms contribute to alcohol sensitivity and alcohol-induced flushing.

 

 

 

레티노산 (retinoic acid)

비타민A(레티놀)의 활성본체(카르본산). all-trans형은 레티노인산수용체 RAR, 9-cis형은RAR, RXR의 배위자로서 작용하며, 호메오박스유전자로 대표하는 표지유전자군의 발현을 전사 수준으로 유도한다. 천연에는 이밖에도 많은 이성질체가 존재하는데 생리활성은 밝혀져있지 않다. 레티날을 경유하는 레티놀부터의 변환이 비타민A의 생리작용발현에 중요하다. 핵 내에서는 RAR, RXR와 세포질에서는 세포질레티노인산결합단백질인 CRABP , Ⅱ과 결합하여 존재한다.

 

레티놀 (retinol)

좁은 뜻으로 비타민A를 말하며, 식물(植物)에서 지방산의 에스테르(육류), 또는 전구체의 카로텐(식물)으로서 섭취하는 지용성 비타민. 소장에서 흡수된 후, 림프액내로지질과 같이 운반되어 간의 비실질 이도(Ito)세포 내의 기름방울 내에 저장된다. 혈중 레티날결합단백질(RBP)과 같이 분비되고 또한 트랜스티레틴(TTR)과 혈중에서 복합체를 형성하여운반되며 표적세포 내에 이입된 후 레티날이나 레티노인산 등의 활성체로 전환되어 효력을 발휘한다

 

 

 Vitamin A metabolism
Living organisms produce retinal (RAL) by irreversible oxidative cleavage of carotenoids. For example
beta-carotene + O2 → 2 retinal
catalyzed by a beta-carotene 15,15'-monooxygenase or a beta-carotene 15,15'-dioxygenase. Just as carotenoids are the precursors of retinal, retinal is the precursor of the other forms of vitamin A. Retinal is interconvertible with retinol (ROL), the transport and storage form of vitamin A
retinal + NADPH + H+ <=>  retinol + NADP+
retinol + NAD+ <=> retinal + NADH + H+
catalyzed by retinol dehydrogenases (RDHs) and alcohol dehydrogenases (ADHs). Retinol is called vitamin A alcohol, or more often, simply vitamin A. Retinal can also be oxidized to retinoic acid (RA)
retinal + NAD+ + H2O → retinoic acid + NADH + H+ (catalyzed by RALDH)
retinal + O2 + H2O → retinoic acid + H2O2 (catalyzed by retinal oxidase)
catalyzed by retinal dehydrogenases also known as retinaldehyde dehydrogenases (RALDHs) as well as retinal oxidases. Retinoic acid, sometimes called vitamin A acid, is an important signaling molecule and hormone in vertebrate animals.

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