Aldehyde Dehydrogenase 1A1 Expression Research Articles

Expression of ALDH1A1 and CD133 is associated with the prognosis and effect of different chemotherapeutic regimens in gastric cancer.

Gastric cancer (GC) is one of the most common malignant tumors worldwide. Previous studies have reported that aldehyde dehydrogenase-1A1 (ALDH1A1) and cluster of differentiation (CD)-133 are considered to be cancer stem cell markers in GCs. The present study immunohistochemically examined the distribution and expression of two tumor stem cell markers, CD133 and ALDH1A1, in both primary tumors and para-tumor tissues. In 91 cases with stage III, 57 (62%) were positive for ALDH1A1 and 60 (66%) were positive for CD133. ALDH1A1 was detected in para-tumors and cancerous tissues of the stomach, and the immunoreactivity of the tumors was stronger than that in para-tumor tissues. CD133 was only detected in tumors. The expression of ALDH1A1 was significantly associated with advanced T/N stage (T stage, P=0.012; N stage, P=0.023) and poor differentiation (P=0.020), while CD133 was associated with advanced T stage (P=0.007). Univariate and multivariate Cox proportional hazards analysis revealed that tumor stage, CD133 expression, vascular invasion and sex were independent predictors of disease-free survival (DFS) time, and tumor size, vascular invasion and sex were independent predictors of overall survival (OS) time in patients with GC. Patients with CD133+ GC had poorer DFS (P=0.042), while ALDH1A1+ GC was not associated with poorer DFS. In regard to chemotherapy, improvements in survival were not observed after the addition of taxane compared with two-drug therapy. However, the subgroup analysis indicated that in the ALDH1A1− subgroup, and CD133+ and ALDH1A1− subgroups, an increased OS was observed in two-drug therapy (P=0.043). The results of the present study indicate that ALDH1A1 and CD133 may play an important role in tumor invasion, metastasis and prognosis, and ALDH1A1− expression does not benefit the taxane-based triple chemotherapeutic regimen in patients with GC.

MiR-625 reverses multidrug resistance in gastric cancer cells by directly targeting ALDH1A1.

Background: microRNAs (miRNAs) are emerging as critical regulators of multidrug resistance (MDR) in gastric cancer, a major cause of chemotherapy failure. miR-625 is downregulated in gastric cancer and negatively associated with metastasis. In the current study, we aimed to investigate whether miR-625 regulates MDR in gastric cancer.Methods: The level of miR-625 in gastric cancer cells with or without MDR was quantified by quantitative reverse transcription PCR (qRT-PCR) analysis. The sensitivity of gastric cancer cells to chemotherapeutic agents was assessed by MTT assay. The protein expression was determined by Western blot analysis, and the luciferase reporter assay was applied to confirm miR-625 regulation of the potential target.Results: miR-625 is downregulated in MDR gastric cancer cells compared with chemosensitive counterparts. In addition, miR-625 increases the sensitivity and promotes apoptosis of gastric cancer cells when treated with different chemotherapeutic agents. Moreover, miR-625 directly targets the aldehyde dehydrogenase 1A1 (ALDH1A1), and importantly, the restoration of ALDH1A1 expression rescues miR-625 effects on MDR in gastric cancer cells.Conclusion: miR-625 reverses MDR in gastric cancer cells by targeting ALDH1A1. Hence, our study identifies miR-625 as a novel regulator of MDR in gastric cancer cells, and implicates its potential application for overcoming MDR in gastric cancer chemotherapy.

Association between Expression of CD133 and Aldehyde Dehydrogenase 1A1 (ALDH1A1) with FIGO Stage in Serous Ovarian Cancer

Ovarian cancer (OC) is the fifth most common cancer in women and has become the main cause of gynecologic malignancy death. The incidence rate of OC increase and overall survival (OS) is relatively low because most of patients are diagnosed at advanced stages. Serous ovarian cancer (SOC) is the most frequent histopathological type and often occurs at late stage. Stage and optimal treatment are independently associated with chemo-response in SOC. FIGO staging system in SOC can provide prognostic information and guidance on personalized management of ovarian cancer. Cancer stem cells (CSC) are pivotal players in SOC progression and prognosis. CD133 and ALDH1A1 are related CSC markers in SOC. This study aimed to investigate the expression of CD133 and ALDH1A1 in SOC and their correlation with FIGO stage. This research was carried out as analytic-observational with cross-sectional design using paraffin block of patients diagnosed with SOC in the Department of Anatomic Pathology Hasan Sadikin Hospital Bandung. Samples were divided in two groups: early stage (FIGO stage I and II) and advanced stage (FIGO stage III and IV). All samples were stained by immunohistochemistry CD133 and ALDH1A1. All data were analysed using Chi-Square test with significant level 5%. The results of this study showed that there was correlation between expression of CD133 with FIGO staging in SOC (p value 0.004) and there was no correlation between expression of ALDH1A1 with FIGO staging in SOC (p value 0.197). It can be concluded that higher CD133 expression showed higher tumour cells ability to do invasion and metastasis and had higher influenced FIGO stage.

Role of ALDH1A1 and HTRA2 expression in CCL2/CCR2-mediated breast cancer cell growth and invasion.

ABSTRACTChemokines mediate immune cell trafficking during tissue development, wound healing and infection. The chemokine CCL2 is best known to regulate macrophage recruitment during wound healing, infection and inflammatory diseases. While the importance of CCL2/CCR2 signaling in macrophages during cancer progression is well documented, we recently showed that CCL2-mediated breast cancer progression depends on CCR2 expression in carcinoma cells. Using 3D Matrigel: Collagen cultures of SUM225 and DCIS.com breast cancer cells, this study characterized the mechanisms of CCL2/CCR2 signaling in cell growth and invasion. SUM225 cells, which expressed lower levels of CCR2 than DCIS.com cells, formed symmetrical spheroids in Matrigel: Collagen, and were not responsive to CCL2 treatment. DCIS.com cells formed asymmetric cell clusters in Matrigel: Collagen. CCL2 treatment increased growth, decreased expression of E-cadherin and increased TWIST1 expression. CCR2 overexpression in SUM225 cells increased responsiveness to CCL2 treatment, enhancing growth and invasion. These phenotypes corresponded to increased expression of Aldehyde Dehydrogenase 1A1 (ALDH1A1) and decreased expression of the mitochondrial serine protease HTRA2. CCR2 deficiency in DCIS.com cells inhibited CCL2-mediated growth and invasion, corresponding to decreased ALDH1A1 expression and increased HTRA2 expression. ALDH1A1 and HTRA2 expression were modulated in CCR2-deficient and CCR2-overexpressing cell lines. We found that ALDH1A1 and HTRA2 regulates CCR2-mediated breast cancer cell growth and cellular invasion in a CCL2/CCR2 context-dependent manner. These data provide novel insight on the mechanisms of chemokine signaling in breast cancer cell growth and invasion, with important implications on targeted therapeutics for anti-cancer treatment.This article has an associated First Person interview with the first author of the paper.

Significance of tumoral and stromal ALDH 1A1 expression in breast invasive duct carcinoma in Egyptian female patients

Background Cancer is considered a stem cell disease. Many stem cell markers are recently well known to have main roles in carcinogenesis and tumor progression. Aldehyde dehydrogenase 1A1 (ALDH1A1) is a stem cell marker that thought to have a role in many cancers. This study aimed to evaluate the expression of ALDH1A1 in different molecular types of breast invasive ductal carcinomas (NOS), and its relation to clinicopathological data. Materials and methods This is a retrospective study carried out on 40 cases of NOS of the breast. The cases were collected from archives of Early Cancer Detection Unit, Benha Faculty of Medicine and Pathology Department, International Medical Center, between the years 2007 and 2013. Previously estrogen receptor, progesterone receptor, Her2/neu and Ki-67 stained slides were reevaluated for each case. Both tumoral and stromal expression of ALDH1A1 was also evaluated for each case. Results A significant positive correlation of ALDH1A1 tumoral expression was observed in patients with age more than 55 years (P Conclusion ALDH1A1 may have a dual role in NOS progression. Also, ALDH1A1 could be used to predict chemoresistant cases among different molecular subtypes. Induction of stromal ALDH1A1 expression could be a possible therapeutic target in the future to suppress tumor progression.

ALDH1A1 expression is associated with poor differentiation, 'right-sidedness' and poor survival in human colorectal cancer.

BackgroundAldehyde dehydrogenase 1A1 (ALDH1A1) encodes an enzyme that oxidizes aldehydes to their corresponding carboxylic acids. In colorectal cancer ALDH1A1 marks cancer stem cells and plays putative roles in tumor progression and drug resistance. However, the potential value of ALDH1A1 as a diagnostic marker or target for therapy remains unclear. Here, we have analyzed ALDH1A1 mRNA and protein levels in relation to clinical, histopathological and molecular tumor features in large series of human colorectal cancer.MethodsALDH1A1 protein levels were determined by immunohistochemistry in a series of primary colorectal tumors and their corresponding liver metastases (n = 158). ALDH1A1 mRNA levels were analyzed in several large patient cohorts of colorectal cancer. ALDH1A1 mRNA and protein levels were then related to overall survival and to clinical, histopathological and molecular tumor features.ResultsHigh levels of ALDH1A1 were associated with a poorly differentiated histology and a right-sided tumor location, but not to a mesenchymal-like molecular subtype. Liver metastases contained significantly higher levels of ALDH1A1 compared to the corresponding primary tumors. Radio- and/or chemotherapy prior to tumor resection was associated with increased ALDH1A1 levels regardless of the molecular subtype. Finally, ALDH1A1 protein expression in primary tumors and metastases correlated with shorter overall survival.ConclusionsALDH1A1 expression is associated with features of poor prognosis, including a poorly differentiated histology and ‘right-sidedness’ of the primary tumor, and with shorter overall survival. ALDH1A1 is also highly expressed in therapy-surviving tumors and in liver metastases. These results warrant further research into the potential value of targeting ALDH1A1 in order to improve the efficacy of standard treatment and thereby preventing tumor recurrence.

Relative expression of aldehyde dehydrogenase 1 family member A1 in different malignancies of human glioma cells

Aldehyde dehydrogenase 1A1 (ALDH1A1) is a cancer stem cell (CSC) marker that plays a role in the differentiation and metastasis of human glioma cells. In this study, we aimed to analyze the expression of ALDH1A1 in different grades of malignancy of human glioma cells. Samples were collected from 32 patients at Cipto Mangunkusumo Hospital, resulting in 19 low-grade glioma (LGG) specimens, 11 high-grade glioma (HGG) specimens, and 2 normal brain specimens. Isolation of RNA was performed prior to the measurement of the relative quantification of ALDH1A1 by using the quantitative reverse transcription polymerase chain reaction (RT-qPCR). There was a trend of higher overexpression of ALDH1A1 in HGG compared to LGG in humans. However, this finding did not reach the level of statistical significance. ALDH1A1 may be a potential marker for malignancy classification. Therefore, further research is needed.

LGR5 and ALDH1A1 served as prognostic and predictive markers for non-small cell lung cancer

Objective To investigate the value of leucine-rich repeat-containing G protein coupled receptor 5 (LGR5) and aldehyde dehydrogenase 1A1 (ALDH1A1) in progression and prognosis of non-small-cell lung cancer (NSCLC), in order to find new targets for NSCLC-targeted imaging and radiation therapy. Methods Fresh tissues (n=24) and paraffin embedding tissues (n=109) of patients with NSCLC were collected from the First Affiliated Hospital of Soochow University between November 2009 and March 2012. Quantitative real time-PCR was used for the investigation of expression of LGR5 and ALDH1A1 mRNA in 24 NSCLC patients. Immunohistochemistry (IHC) was used for detecting LGR5 and ALDH1A1 expressions in NSCLC tissues and adjacent normal tissues. Data were analyzed by Mann-Whitney u test, χ2 test, Pearson correlation analysis, Kaplan-Meier method, Cox proportional hazards regression model. Results Compared with adjacent normal tissues, LGR5 and ALDH1A1 mRNA were frequently increased in NSCLC tissues (u values: 150, 74, both P<0.01), and the expression of LGR5 and ALDH1A1 mRNA was significantly correlated (r=0.416, P<0.05). Positive LGR5 and ALDH1A1 expression was defined in 28.44%(31/109) and 41.28%(45/109) of the NSCLC tumors, respectively. Further analysis indicated that 24 of the LGR5 positive samples (77.42%, 24/31) expressed ALDH1A1 (r=0.388, P<0.01). LGR5 and ALDH1A1 expressions in NSCLC with higher TNM stage were significantly higher than those in NSCLC with lower TNM stage (χ2 values: 4.64, 5.24, both P<0.05). Coexpression of LGR5 and ALDH1A1 in NSCLC with lymph node metastasis was higher than that in NSCLC without lymph node metastasis (χ2=4.12, P<0.05). High expression of LGR5 or ALDH1A1 was related to poor prognosis (χ2 values: 6.24, 4.18, both P<0.05), and NSCLC patients with coexpression of LGR5 and ALDH1A1 had a poorer prognosis than the others (χ2=10.63, P<0.01). Both of them were independent risk factors of a poorer prognosis (corrected hazard ratio (95% CI): 2.361(1.106-5.037), 2.306(1.101-4.830); both P<0.05). Conclusions The expressions of LGR5 and ALDH1A1 are closely associated with the tumorigenesis, metastasis and poor prognosis of NSCLC. LGR5 and ALDH1A1 might be new targets for NSCLC-targeted tumor imaging and radiation therapy. Key words: Carcinoma, non-small-cell lung; Prognosis; Receptors; G-protein-coupled; Aldehyde dehydrogenase

Expression of Aldehyde Dehydrogenase 1A1 (ALDH1A1) as a Prognostic Biomarker in Colorectal Cancer Using Immunohistochemistry.

BackgroundThe expression of aldehyde dehydrogenase 1A1 (ALDH1A1) is increased in several human tumors, including colorectal carcinoma (CRC). The aim of this study was to compare the expression ALDH1A1 in CRC tumor tissue compared with non-tumor adjacent tissue (NAT), using immunohistochemistry (IHC), and to determine whether the expression of the ALDH1A1 protein was associated with prognostic factors in CRC.Material/MethodsFormalin-fixed paraffin-embedded (FFPE) tissue from 424 patients diagnosed with CRC, and 196 matched NATs were used to prepare tissue microarrays (TMAs). IHC was performed using an immunoperoxidase method with a primary polyclonal rabbit anti-ALDH1A1 antibody. The IHC scores by light microscopy were the staining intensity (scored from 0–3) multiplied by the percentage area of positive immunostaining within the visual field (scored from 0–4). Associations between tumor expression levels of ALDH1A1 and patient clinicopathological characteristics, including tumor grade, size, and TNM stage at surgery were analyzed.ResultsALDH1A1 protein expression was significantly increased in CRC tissues compared with matched NATs. In patients with CRC, increased expression of the ALDH1A1 protein was significantly associated with the presence of lymph node metastasis: 64.28% in N0 cases; 75.49% in N1 cases; and 82.14% in N2 cases, (P=0.002). Univariate and multivariate analysis showed that ALDH1A1 expression was an independent prognostic marker for CRC (P<0.001).ConclusionsUsing IHC, the expression of the ALDH1A1 protein in CRC tissues was significantly associated with the presence of lymph node metastases and might be a potential prognostic marker in patients with CRC.

Aldehyde Dehydrogenase 1A1 Expression in Ovarian Epithelial Tumors

Aldehyde Dehydrogenase 1A1 Expression in Ovarian Epithelial Tumors

The role of aldehyde dehydrogenase 1A1 in B-cell non-Hodgkin's lymphoma.

Previously we showed that aldehyde dehydrogenase1A1 (ALDH1A1) is a new mediator for resistance of DLBCL to CHOP and a facility predictor of clinical prognosis. In the present study, knockdown and inhibitor of ALDH1A1 were applied to identify the role of ALDH1A1 in Raji cells. CCK-8 and clone formation assay were applied to determine the CHOP sensitivity and clone formation ability. Caspase colorimetric assay and AnnexinV/FITC staining was performed to determine the degree of apoptosis. Western blot analysis was used to detect the NF-κB/STAT3 signaling proteins and apoptotic-associated proteins. Real-time quantitative PCR (RT-PCR) was used to identify the differential expression of ALDH1A1 between NHL patients and healthy donors. We demonstrated that inhibition of ALDH1A1 increased the sensitivity of Raji cells to CHOP, as indicated by increased cytotoxicity, reduced clonogenicity, activated caspase-3/-9, decreased NF-κB/STAT3 signaling and increased pro-apoptosis signaling, ad increased apoptosis rate. Moreover, we found high ALDH1A1 expression was associated with poor prognosis in NHL patients. Our data revealed the critical role of ALDH1A1 in NHL and provides a theoretical basis for the use of ALDH1A1 inhibitors in NHL patients.

DIC injects €5 M into Fermentalg's development of natural food colorants

Aldehyde dehydrogenase-1A1 (ALDH1A1), CD133, CD44, and CD24 have been reported as cancer stem cell markers in ovarian cancers. The goal of our study was to assess the prognostic significance of these markers in patients with advanced serous ovarian cancer. Formalin-fixed, paraffin-embedded tissues from 347 ovarian cancers were used to construct a microarray. Immunohistochemical studies for ALDH1A1, CD133, CD44, and CD24 were performed and scored semiquantitatively by 2 pathologists based on intensity and percent of positive immunoreactive cells. Immunohistochemistry was compared to clinical parameters and survival. Of the 347 cases, early stage disease, nonserous tumors, cases with incomplete therapy, and cores with no tumor were excluded. Immunohistochemistry was interpretable in 124 of the 136 stage III and IV ovarian serous carcinoma. ALDH1A1, CD24, and CD44 were variably detected in both tumor and stromal cells, and immunoreactivity in tumor was stronger than in stromal cells. CD133 immunoreactivity was not quantified due to nonspecific staining in tumor and stroma. Statistical analyses using χ2 and Student t test revealed that ALDH1A1-positive (n = 53) carcinoma were 3 times more likely to demonstrate platinum refractoriness than ALDH1A1-negative (n = 71) tumors (17% vs. 6%, respectively; p = .04); however, neither progression free nor overall survival was influenced by ALDH1A1 status in this cohort. The expression of CD44 and CD24 had no clinicopathological associations in the present study. Our study supports that ALDH1A1 expression is associated with poor response to platinum-based therapy in patients with high-grade ovarian serous carcinoma. Further study of this relationship is needed to understand how this could impact clinical care.

Aldehyde dehydrogenase 1A1 (ALDH1A1) expression by immunohistochemistry is associated with chemo-refractoriness in patients with high-grade ovarian serous carcinoma

Aldehyde dehydrogenase-1A1 (ALDH1A1), CD133, CD44, and CD24 have been reported as cancer stem cell markers in ovarian cancers. The goal of our study was to assess the prognostic significance of these markers in patients with advanced serous ovarian cancer. Formalin-fixed, paraffin-embedded tissues from 347 ovarian cancers were used to construct a microarray. Immunohistochemical studies for ALDH1A1, CD133, CD44, and CD24 were performed and scored semiquantitatively by 2 pathologists based on intensity and percent of positive immunoreactive cells. Immunohistochemistry was compared to clinical parameters and survival. Of the 347 cases, early stage disease, nonserous tumors, cases with incomplete therapy, and cores with no tumor were excluded. Immunohistochemistry was interpretable in 124 of the 136 stage III and IV ovarian serous carcinoma. ALDH1A1, CD24, and CD44 were variably detected in both tumor and stromal cells, and immunoreactivity in tumor was stronger than in stromal cells. CD133 immunoreactivity was not quantified due to nonspecific staining in tumor and stroma. Statistical analyses using χ2 and Student t test revealed that ALDH1A1-positive (n=53) carcinoma were 3 times more likely to demonstrate platinum refractoriness than ALDH1A1-negative (n=71) tumors (17% vs. 6%, respectively; p=.04); however, neither progression free nor overall survival was influenced by ALDH1A1 status in this cohort. The expression of CD44 and CD24 had no clinicopathological associations in the present study. Our study supports that ALDH1A1 expression is associated with poor response to platinum-based therapy in patients with high-grade ovarian serous carcinoma. Further study of this relationship is needed to understand how this could impact clinical care.

Aldehyde dehydrogenase 1A1 increases NADH levels and promotes tumor growth via glutathione/dihydrolipoic acid-dependent NAD+ reduction.

Aldehyde dehydrogenase 1A1 (ALDH1A1) is a member of the aldehyde dehydrogenase superfamily that oxidizes aldehydes to their corresponding acids, reactions that are coupled to the reduction of NAD+ to NADH. We report here that ALDH1A1 can also use glutathione (GSH) and dihydrolipoic acid (DHLA) as electron donors to reduce NAD+ to NADH. The GSH/DHLA-dependent NAD+-reduction activity of ALDH1A1 is not affected by the aldehyde dehydrogenase inhibitor or by mutation of the residues in its aldehyde-binding pocket. It is thus a distinct biochemical reaction from the classic aldehyde-dehydrogenase activity catalyzed by ALDH1A1. We also found that the ectopic expression of ALDH1A1 decreased the intracellular NAD+/NADH ratio, while knockout of ALDH1A1 increased the NAD+/NADH ratio. Simultaneous knockout of ALDH1A1 and its isozyme ALDH3A1 in lung cancer cell line NCI-H460 inhibited tumor growth in a xenograft model. Moreover, the ALDH1A1 mutants that retained their GSH/DHLA-dependent NAD+ reduction activity but lost their aldehyde-dehydrogenase activity were able to decrease the NAD+/NADH ratio and to rescue the impaired growth of ALDH1A1/3A1 double knockout tumor cells. Collectively, these results suggest that this newly characterized GSH/DHLA-dependent NAD+-reduction activity of ALDH1A1 can decrease cellular NAD+/NADH ratio and promote tumor growth.

The Clinical Significance of Cancer Stem Cell Markers ALDH1A1 and CD133 in Lung Adenocarcinoma.

Aldehyde dehydrogenase-1A1 (ALDH1A1) and CD133 have been identified as markers of cancer stem cells (CSCs). We investigated the expression of these markers and their clinical significance in lung adenocarcinoma. An immunohistochemical analysis of ALDH1A1 and CD133 expression of 92 lung adenocarcinomas was performed. The association between the expression of both markers and cancer-related death and recurrence was determined. Cancer-related death and tumor recurrence were observed in 15 and 17 cases, respectively. The expression of CD133, but not ALDHA1A, was significantly associated with poorer overall survival (p<0.0001) and shorter disease-free interval (DFI) (p<0.0001). Multivariate analysis revealed that double negativity was independently associated with increased survival (hazard ratio(HR)=16.1, p=0.0004) and a longer DFI (HR=9.5, p=0.0007). We propose that as a functional marker, ALDH1A1 positivity may influence the viability of CSCs. The findings suggest that it is important to evaluate the expression of both markers.

Targeted therapy for a subset of acute myeloid leukemias that lack expression of aldehyde dehydrogenase 1A1.

Aldehyde dehydrogenase 1A1 (ALDH1A1) activity is high in hematopoietic stem cells and functions in part to protect stem cells from reactive aldehydes and other toxic compounds. In contrast, we found that approximately 25% of all acute myeloid leukemias expressed low or undetectable levels of ALDH1A1 and that this ALDH1A1− subset of leukemias correlates with good prognosis cytogenetics. ALDH1A1− cell lines as well as primary leukemia cells were found to be sensitive to treatment with compounds that directly and indirectly generate toxic ALDH substrates including 4-hydroxynonenal and the clinically relevant compounds arsenic trioxide and 4-hydroperoxycyclophosphamide. In contrast, normal hematopoietic stem cells were relatively resistant to these compounds. Using a murine xenotransplant model to emulate a clinical treatment strategy, established ALDH1A1− leukemias were also sensitive to in vivo treatment with cyclophosphamide combined with arsenic trioxide. These results demonstrate that targeting ALDH1A1− leukemic cells with toxic ALDH1A1 substrates such as arsenic and cyclophosphamide may be a novel targeted therapeutic strategy for this subset of acute myeloid leukemias.

Depleted aldehyde dehydrogenase 1A1 (ALDH1A1) reverses cisplatin resistance of human lung adenocarcinoma cell A549/DDP.

BackgroundCisplatin is the standard first‐line chemotherapeutic agent for the treatment of non‐small cell lung cancer (NSCLC). However, resistance to chemotherapy has been a major obstacle in the management of NSCLC. Aldehyde dehydrogenase 1A1 (ALDH1A1) overexpression has been observed in a variety of cancers, including lung cancer. The purpose of this study was to investigate the effect of ALDH1A1 expression on cisplatin resistance and explore the mechanism responsible.MethodsReverse transcriptase‐PCR was applied to measure the messenger RNA expression of ALDH1A1, while Western blot assay was employed to evaluate the protein expression of ALDH1A1, B‐cell lymphoma 2, Bcl‐2‐like protein 4, phospho‐protein kinase B (p‐AKT) and AKT. A short hairpin RNA was used to knockdown ALDH1A1 expression. A 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay was used to determine the effect of ALDH1A1 decrease on cell viability. The cell apoptotic rate was tested using flow cytometry assay.Results ALDH1A1 is overexpressed in cisplatin resistant cell line A549/DDP, compared with A549. ALDH1A1 depletion significantly decreased A549/DDP proliferation, increased apoptosis, and reduced cisplatin resistance. In addition, the phosphoinositide 3‐kinase (PI3K) / AKT pathway is activated in A549/DDP, and ALDH1A1 knockdown reduced the phosphorylation level of AKT. Moreover, the combination of ALDH1A1‐short hairpin RNA and PI3K/AKT pathway inhibitor LY294002 markedly inhibited cell viability, enhanced apoptotic cell death, and increased cisplatin sensitivity.ConclusionThese results suggest that ALDH1A1 depletion could reverse cisplatin resistance in human lung cancer cell line A549/DDP, and may act as a potential target for the treatment of lung cancers resistant to cisplatin.

In phyllodes tumour of the breast expression of c-kit but not of ALDH1A1 is associated with adverse clinico-pathological features.

Attempts at identification of an ideal prognostic/predictive biomarker in phyllodes tumour (PT) have not been fruitful so far. Studies evaluating c-kit expression in PT have shown contradictory results. Recently aldehyde dehydrogenase 1A1 (ALDH1A1) was proposed as a stem cell marker for malignant PT but its expression has not been studied in benign and borderline tumours. We aimed to evaluate expression and prognostic significance of c-kit and ALDH1A1 in different grades of PT. Epithelial and stromal c-kit and ALDH1A1 expression were studied in 104 PT cases (86 primary and 18 recurrent tumours) and compared with different clinico-pathological features and recurrence rates. Stromal c-kit expression at 1% cutoff correlated with increasing tumour grade, larger tumour size, hypercellularity, nuclear atypia, stromal overgrowth, infiltrative margins and mitotic count. These associations, however, were lost with higher (5 or 10%) cutoffs. Conversely, decreased c-kit expression in the epithelial component correlated with increasing tumour grade, regardless of the cutoffs used. Stromal ALDH1A1 expression did not have significant associations with tumour grade or other adverse clinico-pathological features, regardless of different cutoffs. None of the cases showed significant epithelial ALDH1A1 expression. Expression of c-kit was associated with poorer overall survival (p=0.011), while ALDH1A1 expression was associated with shorter recurrence-free survival (p=0.036). In conclusion, c-kit expression was associated with higher tumour grade and adverse clinico-pathological features. However, these associations are cutoff dependent, partly explaining the variability in previously reported studies. ALDH1A1 expression did not have significant correlations with tumour grade and adverse clinico-pathological variables.

Expression changes of aldehyde dehydrogenase 1A1 in rat cryptorchidism and normal testis

Objective: To study the mRNA and protein expression of aldehyde dehydrogenase 1A1(ALDH1A1)in rat cryptorchidism and normal testis. Methods: We established the cryptorchidism model by flutamide and took normal testis as normal group.The testicular tissue samples were collected on 15 days, 45 days, and 90 days after birth respectively.The expression of ALDH1A1 in rat cryptorchidism and normal testis were investigated by real-time PCR, Western blot and immunohistochemisty intissue microarray. Results: The mRNA expression of ALDH1A1 in cryptorchidism group in infant, adolescent and adult period were 1.01±0.19, 1.60±0.32, 0.75±0.16, and 1.66±0.23, 0.52±0.08, 0.15±0.10 in normal group, respectively.The expression of ALDH1A1 in cryptorchidism group was significantly lower than that in normal group in infant period, but it was significantly higher than that in the normal group in adolescent and adult period(P<0.05). Conclusions: The expression of ALDH1A1 was different in different age period during the process of testicular development of rat. It showed an important relationship between ALDH1A1 and cryptorchidism.

ALDH1A1 induces resistance to CHOP in diffuse large B-cell lymphoma through activation of the JAK2/STAT3 pathway.

Increasing evidence has shown that aldehyde dehydrogenase 1A1 (ALDH1A1), a detoxifying enzyme, is responsible for chemoresistance in a variety of tumors. Although the majority of patients with diffuse large B-cell lymphoma (DLBCL) can be cured with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), chemoresistance is a common cause of treatment failure. This study aims to investigate the significance of ALDH1A1 expression and the mechanism by which ALDH1A1 is involved in the chemoresistance of DLBCL cells. ALDH1A1 expression was assessed in 88 DLBCL tissues by immunohistochemistry. The association between ALDH1A1 expression and outcome was evaluated. We also investigated the effect of ALDH1A1 on CHOP resistance in DLBCL cells using functional analysis. ALDH1A1 expression levels were upregulated in patients with stable or progressive disease after CHOP and its expression positively correlated with expression of STAT3 and p-STAT3. In keeping with these observations, ALDH1A1 expression was significantly associated with short survival of DLBCL patients who received CHOP chemotherapy. In functional assays in Pfeiffer cells, overexpression of ALDH1A1 conferred resistance to CHOP, while silencing of ALDH1A1 using short hairpin RNA had the opposite effect. Furthermore, we also observed that ALDH1A1 could regulate the JAK2/STAT3 pathway, while inhibition of the JAK2/STAT3 pathway by WP1066 negated the effect of ALDH1A1 overexpression. These observations reveal that ALDH1A1 induces resistance to CHOP through activation of the JAK2/STAT3 pathway in DLBCL, and its targeting provides a potential strategic approach for reversing CHOP resistance.