Impaired Self-Renewal and Increased Colitis and Dysplastic Lesions in Colonic Mucosa of AKR1B8-Deficient Mice

Shen, Yi; Ma, Jun; Yan, Ruilan; Ling, Hong-Yan; Li, Xiaoning; Yang, Wancai; Gao, Jianxi; Huang, Chenfei; Bu, Yiwen; Cao, Yu; He, Yingchun; Wan, Laxiang; Zu, Xuyu; Liu, Jianghua; Huang, Mei; Stenson, William F.; Liao, Duan‐Fang; Cao, Deliang

doi:10.1158/1078-0432.ccr-14-2072

Cited by 48 publications

(73 citation statements)

References 50 publications

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“…Very recently, we found that AKR1B10 stimulates metastasis of breast cancer through integrin α5/δ‐catenin mediated FAK/Src/Rac1 signaling pathway . In normal tissues, AKR1B10 is primarily expressed in the colon and small intestine, where it regulates proliferation and self‐renewal of cryptic epithelial cells …”

Section: Introductionmentioning

confidence: 99%

AKR1B10 activates diacylglycerol (DAG) second messenger in breast cancer cells

Huang

Cao

et al. 2018

Molecular Carcinogenesis

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Aldo-keto reductase 1B10 (AKR1B10) is upregulated in breast cancer and promotes tumor growth and metastasis. However, little is known of the molecular mechanisms of action. Herein we report that AKR1B10 activates lipid second messengers to stimulate cell proliferation. Our data showed that ectopic expression of AKR1B10 in breast cancer cells MCF-7 promoted lipogenesis and enhanced levels of lipid second messengers, including phosphatidylinositol bisphosphate (PIP2), diacylglycerol (DAG), and inositol triphosphate (IP3). In contrast, silencing of AKR1B10 in breast cancer cells BT-20 and colon cancer cells HCT-8 led to decrease of these lipid messengers. Qualitative analyses by liquid chromatography-mass spectrum (LC-MS) revealed that AKR1B10 regulated the cellular levels of total DAG and majority of subspecies. This in turn modulated the phosphorylation of protein kinase C (PKC) isoforms PKCδ (Thr505), PKCµ (Ser744/748), and PKCα/βII (Thr638/641) and activity of the PKC-mediated c-Raf/MEK/ERK signaling cascade. A pan inhibitor of PKC (Go6983) blocked ERK1/2 activation by AKR1B10. In these cells, phospho-p90RSK, phospho-MSK, and Cyclin D1 expression was increased by AKR1B10, and pharmacological inhibition of the ERK signaling cascade with MEK1/2 inhibitors U0126 and PD98059 eradicated induction of phospho-p90RSK, phospho-MSK, and Cyclin D1. In breast cancer cells, AKR1B10 promoted the clonogenic growth and proliferation of breast cancer cells in two-dimension (2D) and three-dimension (3D) cultures and tumor growth in immunodeficient female nude mice through activation of the PKC/ERK pathway. These data suggest that AKR1B10 stimulates breast cancer cell growth and proliferation through activation of DAG-mediated PKC/ERK signaling pathway.

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Section: Introductionmentioning

confidence: 99%

AKR1B10 activates diacylglycerol (DAG) second messenger in breast cancer cells

Huang

Cao

et al. 2018

Molecular Carcinogenesis

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“…In normal tissues, AKR1B10 is primarily expressed in the colon and small intestine and promotes epithelial cell proliferation regulating epithelial cell self-renewal [16, 24]. Targeted disruption of AKR1B8 (an ortholog of AKR1B10 in mouse) leads to diminished proliferation and migration of epithelial cells and increased susceptibility to carbonyl and oxidative stress-induced DNA damage and tumorigenesis [25]. In tumors, AKR1B10 is upregulated in breast, liver and lung cancers, promoting tumor growth and progression [26–29].…”

Section: Introductionmentioning

confidence: 99%

AKR1B10 promotes breast cancer metastasis through integrin α5/δ-catenin mediated FAK/Src/Rac1 signaling pathway

et al. 2016

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Aldo-keto reductase 1B10 (AKR1B10) is not expressed in normal breast, but upregulated in primary and metastatic breast cancers, being a negative prognostic factor. This study characterized the molecular mechanisms of AKR1B10-promoted breast cancer metastasis. Ectopic expression of AKR1B10 in breast cancer cells MCF-7 and MDA-MB-231 or siRNA-mediated silencing in BT-20 cells affected cell adhesion, migration and invasion in cell culture, and metastasis to the lung in the nude mice through upregulation of integrin α5 and δ-catenin. Silencing of integrin α5 or δ-catenin eradicated the cell adhesion and migration enhanced by AKR1B10, both of which acted synergistically. In these cells, the integrin α5 mediated focal adhesion kinase (FAK) signaling pathway was activated by AKR1B10, which, along with δ-catenin, stimulated Rac1-mediated cell migration and movement. In human primary and lymph node metastatic breast cancer, AKR1B10, integrin α5 and δ-catenin were correlatively upregulated with r=0.645 (p<0.0001) and r=0.796 (p<0.0001), respectively. These data suggest that AKR1B10 promotes breast cancer metastasis through activation of the integrin α5 and δ-catenin mediated FAK/Src/Rac1 signaling pathway.

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“…AKR1B10 is a secretory protein up‐regulated in HCC . AKR1B10 can eliminate cytotoxic and carcinogenic α and β‐unsaturated carbonyl compounds and regulate de novo fatty acid/lipid synthesis . In normal tissues, AKR1B10 is specifically expressed in the colon and small intestine, where it is secreted into the lumen .…”

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confidence: 99%

A Large‐Scale Multicenter Study Validates Aldo‐Keto Reductase Family 1 Member B10 as a Prevalent Serum Marker for Detection of Hepatocellular Carcinoma

et al. 2019

Hepatology

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Aldo‐keto reductase family 1 member B10 (AKR1B10) is a secretory protein overexpressed in hepatocellular carcinoma (HCC). We aimed to evaluate AKR1B10 as a serum marker for detection of HCC. Herein, we conducted a cohort study that consecutively enrolled 1,244 participants from three independent hospitals, including HCC, healthy controls (HCs), benign liver tumors (BLTs), chronic hepatitis B (CHB), and liver cirrhosis (LC). Serum AKR1B10 was tested by time‐resolved fluorescent assays. Data were plotted for receiver operating characteristic (ROC) curve analyses. Alpha‐fetoprotein (AFP) was analyzed for comparison. An exploratory discovery cohort demonstrated that serum AKR1B10 increased in patients with HCC (1,567.3 ± 292.6 pg/mL; n = 69) compared with HCs (85.7 ± 10.9 pg/mL; n = 66; P < 0.0001). A training cohort of 519 participants yielded an optimal diagnostic cutoff of serum AKR1B10 at 267.9 pg/mL. When ROC curve was plotted for HCC versus all controls (HC + BLT + CHB + LC), serum AKR1B10 had diagnostic parameters of the area under the curve (AUC) 0.896, sensitivity 72.7%, and specificity 95.7%, which were better than AFP with AUC 0.816, sensitivity 65.1%, and specificity 88.9%. Impressively, AKR1B10 showed promising diagnostic potential in early‐stage HCC and AFP‐negative HCC. Combination of AKR1B10 with AFP increased diagnostic accuracy for HCC compared with AKR1B10 or AFP alone. A validation cohort of 522 participants confirmed these findings. An independent cohort of 68 patients with HCC who were followed up showed that serum AKR1B10 dramatically decreased 1 day after operation and was nearly back to normal 3 days after operation. Conclusion : AKR1B10 is a potent serum marker for detection of HCC and early‐stage HCC, with better diagnostic performance than AFP.

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Impaired Self-Renewal and Increased Colitis and Dysplastic Lesions in Colonic Mucosa of AKR1B8-Deficient Mice

Cited by 48 publications

References 50 publications

AKR1B10 activates diacylglycerol (DAG) second messenger in breast cancer cells

AKR1B10 activates diacylglycerol (DAG) second messenger in breast cancer cells

AKR1B10 promotes breast cancer metastasis through integrin α5/δ-catenin mediated FAK/Src/Rac1 signaling pathway

A Large‐Scale Multicenter Study Validates Aldo‐Keto Reductase Family 1 Member B10 as a Prevalent Serum Marker for Detection of Hepatocellular Carcinoma

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