Elevated Serum Angiopoietin-like Protein 2 Correlates with the Metastatic Properties of Colorectal Cancer: A Serum Biomarker for Early Diagnosis and Recurrence

Toiyama, Yuji; Tanaka, Koji; Kitajima, Takahito; Shimura, Takaya; Kawamura, Mikio; Kawamoto, Aya; Okugawa, Yoshinaga; Saigusa, Susumu; Hiro, Junichirou; Inoue, Yasuhiro; Mohri, Yasuhiko; Goel, Ajay; Kusunoki, Masato

doi:10.1158/1078-0432.ccr-14-0007

Cited by 44 publications

(47 citation statements)

References 33 publications

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“…Further intervention studies show that targeted inhibition of Ang2 can inhibit tumor angiogenesis and lymphangiogenesis. Therefore, Ang2 may be the potential target for anticancer therapy . By performing luciferase reporter gene assay and western blot, this study confirmed the regulatory ability of miR‐93 on Ang2 expression on both molecular level and protein level.…”

Section: Discussionsupporting

confidence: 64%

The role of microRNA‐93 regulating angiopoietin2 in the formation of malignant pleural effusion

et al. 2017

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The biological roles of miRNAs in the development of malignant pleural effusion (MPE) are unclear. In this study, the miRNA microarray analysis was performed in two different prognosis groups of lung adenocarcinoma patients. Expression profiles of miRNAs in MPEs were identified. With the help of quantification PCR, we confirmed the expression differences of miRNAs and further analyzed their biological functions and relative target genes in vitro. The target gene of miR‐93 was estimated by online database, and also, the protein was tested. The target gene and the binding sites of specific miRNA were estimated by online database. The combining capacity of binding sites was verified by luciferase reporter gene assay, and the target gene protein was tested by western blot. We detected 107 miRNAs with expression differences (n = 10) and confirmed significant expression differences in miR‐93 and miR‐146a in two groups of patients (n = 84). By manipulating miR‐93 expression of human lymphatic endothelial cells (HLEC) and human umbilical vein endothelial cells (HUVEC), we discovered that high expression of miR‐93 inhibited migration, proliferation, and angiogenesis. And also, miR‐93 increased not only apoptosis, but also G1 phase cell block. By using luciferase reporter gene assay and western blot, we confirmed that angiopoietin2 (Ang2) was the target of miR‐93. The data showed that miR‐93 has an inhibiting effect on pleural effusion. By targeting Ang2, miR‐93 regulates angiogenesis and lymphangiogenesis and plays a role in pathogenetic mechanism of MPE. MiR‐93/Ang2 may shed light on potential new targets in cancer treatment.

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Section: Discussionsupporting

confidence: 64%

The role of microRNA‐93 regulating angiopoietin2 in the formation of malignant pleural effusion

et al. 2017

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“…KRAS (exons 2 and 3) and BRAF (V600E) mutations were analyzed by pyrosequencing as previously described (26). The list of primers used is found in Supplementary Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

Microsatellite Alterations With Allelic Loss at 9p24.2 Signify Less-Aggressive Colorectal Cancer Metastasis

et al. 2016

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Background & Aims Molecular events that lead to recurrence and/or metastasis after curative treatment of patients with colorectal cancers (CRCs) are poorly understood. Patients with stage II or III primary CRC with increased numbers of microsatellite alterations at selected tetra-nucleotide repeats (EMAST) and low levels of microsatellite instability (E/L) are more likely to have disease recurrence after treatment. Hypoxia and/or inflammation not only promote metastasis but also induce EMAST by causing deficiency of MSH3 in the cancer cell nucleus. We aimed to identify genetic alterations associated with metastasis of primary colorectal tumors to liver and to determine their effects on survival. Methods We obtained 4 sets of primary colorectal tumors and matched liver metastases from hospitals in Korea and Japan. Intragenic microsatellites with large repeats at 141 loci were examined for frame-shift mutations and/or loss of heterozygosity (LOH) as possible consequences of MSH3 deficiency. Highly altered loci were examined for association with E/L in liver metastases. We analyzed data from 156 of the patients with stage II or III primary colorectal tumors to determine outcomes and whether altered loci were associated with E/L. Results LOH at several loci at chromosome 9p24.2 (9p24.2-LOH) was associated with E/L in liver metastases (odds ratio, 10.5; 95% confidence interval [CI], 2.69–40.80; P=.0007). We found no significant difference in the frequency of E/L, 9p24.2-LOH, mutations in KRAS or BRAF, or the combination of E/L and 9p24.2-LOH between primary colorectal tumors and their matched metastases. Patients with stage II or III colorectal tumors with E/L and 9p24.2-LOH had increased survival following CRC recurrence (hazard ratio, 0.25; 95% CI, 0.12–0.50; P=.0001), compared to patients without with E/L and 9p24.2-LOH. E/L with 9p24.2-LOH appeared to be an independent prognostic factor for overall survival of patients with stage III CRC (hazard ratio, 0.06; 95% CI, 0.01–0.57; P=.01). Conclusions E/L with 9p24-LOH appears to be a biomarker for less aggressive metastasis from stage III primary colorectal tumors.

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“…29 Circulating ANGPTL2 levels increase with age in Japanese populations 25 and are high in patients with chronic, age-associated diseases, such as heart disease, kidney disease, diabetes, and cancer. 21,29- 35 Previous studies have shown that ANGPTL2 potently promotes pro-angiogenic and anti-apoptotic activities, as do the ANGPTs. 28,36,37 Moreover, we reported that ANGPTL2 signaling through integrin α5β1 enhances cell motility by activating the Rho family GTPase Rac1 and by stimulating remodeling of the extracellular matrix (ECM) through activation of p38 mitogen-activated protein kinase (MAPK)-dependent matrix metalloproteinases (MMPs) (Figure 1).…”

Section: Angptl2 Function In Cvd Development and Progressionmentioning

confidence: 99%

“…As noted earlier, circulating ANGPTL2 levels increase with age in Japanese populations 25 and are high in patients with chronic, age-associated diseases such as heart disease, kidney disease, diabetes, and cancer. 21,29- 35 Thus, ANGPTL2 may function as a SASP in several senescent cell types. If so, markedly increased circulating ANGPTL2 levels seen in patients with chronic aging-related diseases may reflect the accumulation of senescent cells in their organs.…”

Section: Angptl2 Expression Is Associated With Cellular Senescencementioning

confidence: 99%

ANGPTL2　― A New Causal Player in Accelerating Heart Disease Development in the Aging ―

Oike

Tian

Miyata

et al. 2017

Circ J

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inflammation, 11,12 and emerging evidence reveals that senescent cells secrete factors that cause chronic local tissue inflammation associated with age-associated diseases. [13][14][15] This newly identified cellular senescence condition, termed the senescence-associated secretory phenotype (SASP), is now recognized as creating a common pathological environment that encourages development of age-associated diseases, including CVD. 13,15, 16 Many of our previous studies have revealed that the expression and secretion of angiopoietin-like 2 (ANGPTL2) significantly increase in cells stressed by pathophysiologic stimuli such as hypoxia, reactive oxidative species, and pressure overload. 17-21 ANGPTL2 expression also increases in cells undergoing senescence, 22 suggesting that ANGPTL2 is a SASP factor. Moreover, excess ANGPTL2 signaling is pro-inflammatory in pathologic states and contributes to the development of aging-associated diseases such as CVD. 23-25 Thus, to understand the mechanisms underlying these conditions, we focus our discussion here on the role of ANGPTL2 in CVD. What Is ANGPTL2?Around 2000, several groups independently reported secreted glycoproteins that exhibit an N-terminal coiled-coil W orldwide, the number of patients with heart disease is increasing as populations of elderly people expand. Of the heart diseases, cardiovascular disease (CVD) and heart failure (HF) are associated with adverse health outcomes that decrease a patient's wellbeing and productivity. 1,2 Prevention of these conditions is desirable to promote healthy aging and improve patients' lifestyle.The pathologic basis of CVD is atherosclerosis caused by ectopic accumulation of cholesterol in vessel walls; 3 thus advent of therapies aimed at reducing low-density lipoprotein (LDL)-cholesterol levels has succeeded in decreasing the number of CVD events. 4,5 However, these events continue to occur, even in patients whose LDLcholesterol levels have been lowered by antidyslipidemia treatment, 1,2,4,5 indicating that the pathologies underlying CVD are highly complex. In addition to dyslipidemia, other factors such as smoking, hypertension, diabetes, ventral obesity, male sex, aging, genetic factors, and family history of CVD are well-established risk factors, 6-8 and the number of patients with dyslipidemia, diabetes, and hypertension also increases with age. 9 Recently, it was shown that chronic vascular inflammation accelerates atherosclerosis development. 10 Interestingly, aging, smoking, diabetes, and dyslipidemia all induce chronic In parallel with the increase in the number of elderly people worldwide, the number of patients with heart disease is also rapidly increasing. Of the heart diseases, cardiovascular disease (CVD) and heart failure (HF) are strongly associated with adverse health outcomes that decrease productivity in later years. Recently, ANGPTL2, a secreted glycoprotein and member of the angiopoietin-like protein family, has received attention as a causal player in the development of CVD and HF. Prolonged ANGPTL2 auto...

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Elevated Serum Angiopoietin-like Protein 2 Correlates with the Metastatic Properties of Colorectal Cancer: A Serum Biomarker for Early Diagnosis and Recurrence

Cited by 44 publications

References 33 publications

The role of microRNA‐93 regulating angiopoietin2 in the formation of malignant pleural effusion

The role of microRNA‐93 regulating angiopoietin2 in the formation of malignant pleural effusion

Microsatellite Alterations With Allelic Loss at 9p24.2 Signify Less-Aggressive Colorectal Cancer Metastasis

ANGPTL2　― A New Causal Player in Accelerating Heart Disease Development in the Aging ―

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Elevated Serum Angiopoietin-like Protein 2 Correlates with the Metastatic Properties of Colorectal Cancer: A Serum Biomarker for Early Diagnosis and Recurrence

Cited by 44 publications

References 33 publications

The role of microRNA‐93 regulating angiopoietin2 in the formation of malignant pleural effusion

The role of microRNA‐93 regulating angiopoietin2 in the formation of malignant pleural effusion

Microsatellite Alterations With Allelic Loss at 9p24.2 Signify Less-Aggressive Colorectal Cancer Metastasis

ANGPTL2 ― A New Causal Player in Accelerating Heart Disease Development in the Aging ―

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ANGPTL2　― A New Causal Player in Accelerating Heart Disease Development in the Aging ―