Metastasis-associated protein 1 induces VEGF-C and facilitates lymphangiogenesis in colorectal cancer

AIM:To study the correlation between high metastasisassociated protein 1(MTA1)expression and lymphangiogenesis in colorectal cancer(CRC)and its role in production of vascular endothelial growth factor-C(VEGF-C). METHODS:Impact of high MTA1 and VEGF-C expression levels on disease progression and lymphovasculardensity(LVD,D2-40-immunolabeled)in 81 cases of human CRC was evaluated by immunohistochemistry. VEGF-C mRNA and protein expressions in human LoVo and HCT116 cell lines were detected by real-time polymerase chain reaction and Western blotting,respectively,with a stable expression vector or siRNA. RESULTS:The elevated MTA1 and VEGF-C expression levels were correlated with lymph node metastasis and Dukes stages(P<0.05).Additionally,high MTA1 expression level was correlated with a large tumor size(P< 0.05).A significant correlation was found between MTA1 and VEGF-C protein expressions in tumor cells(r=0.371, P<0.05).Similar to the VEGF-C expression level,high MTA1 expression level was correlated with high LVD in CRC(P<0.05).Furthermore,over-expression of MTA1 significantly enhanced the VEGF-C mRNA and protein expression levels,whereas siRNAs-knocked down MTA1 decreased the VEGF-C expression level. CONCLUSION:MTA1,as a regulator of tumor-associated lymphangiogenesis,promotes lymphangiogenesis in CRC by mediating the VEGF-C expression.

Metastasis-associated in colon cancer-1 in gastric cancer: Beyond metastasis

Metastasis-associated in colon cancer-1(MACC1) is an oncogene that was first identified in colon cancer. The upstream and downstream of MACC1 form a delicate regulatory network that supports its tumorigenic role in cancers. Multiple functions of MACC1 have been discovered in many cancers. In gastric cancer(GC), MACC1 has been shown to be involved in oncogenesis and t umor progression. MACC1 overexpression adversely affects the clinical outcomes of GC patients. Regarding the mechanism of action of MACC1 in GC, studies have shown that it promotes the epithelialto-mesenchymal transition and accelerates cancer metastasis. MACC1 is involved in many hallmarks of GC in addition to metastasis. MACC1 promotes vasculogenic mimicry(VM) via TWIST1/2, and VM increases the tumor blood supply, which is necessary for tumor progression. MACC1 also facilitates GC lymphangiogenesis by upregulating extracellular secretion of VEGF-C/D, indicating that MACC1 may be an important player in GC lymphatic dissemination. Additionally, MACC1 supports GC growth under metabolic stress by enhancing the Warburg effect. In conclusion, MACC1 participates in multiple biological processes inside and outside of GC cells, making it an important mediator of the tumor microenvironment.

Correlation between the expressions of metastasis-associated factor-1 in colon cancer and vacuolar ATP synthase

BACKGROUND Clinical prognosis often worsens due to high recurrence rates following radical surgery for colon cancer.The examination of high-risk recurrence factors post-surgery provides critical insights for disease evaluation and treatment planning.AIM To explore the relationship between metastasis-associated factor-1 in colon cancer(MACC1)and vacuolar ATP synthase(V-ATPase)expression in colon cancer tissues,and recurrence rate in patients undergoing radical colon cancer surgery.METHODS We selected 104 patients treated with radical colon cancer surgery at our hospital from January 2018 to June 2021.Immunohistochemical staining was utilized to assess the expression levels of MACC1 and V-ATPase in these patients.RESULTS The rates of MACC1 and V-ATPase positivity were 64.42%and 67.31%,respe-ctively,in colon cancer tissues,which were significantly higher than in paracan-cerous tissues(P<0.05).Among patients with TNM stage III,medium to low differentiation,and lymph node metastasis,the positive rates of MACC1 and V-ATPase were significantly elevated in comparison to patients with TNM stage I-II,high differentiation,and no lymph node metastasis(P<0.05).The rate of MACC1 positivity was 76.67%in patients with tumor diameters>5 cm,notably higher than in patients with tumor diameters≤5 cm(P<0.05).We observed a positive correlation between MACC1 and V-ATPase expression(rs=0.797,P<0.05).The positive rates of MACC1 and V-ATPase were significantly higher in patients with recurrence compared to those without(P<0.05).Logistic regression analysis revealed TNM stage,lymph node metastasis,MACC1 expression,and V-ATPase expression as risk factors for postoperative colon cancer recurrence(OR=6.322,3.435,2.683,and 2.421;P<0.05).CONCLUSION The upregulated expression of MACC1 and V-ATPase in colon cancer patients appears to correlate with clinicopathological features and post-radical surgery recurrence.

Silencing MTA1 by RNAi Reverses Adhesion, Migration and Invasiveness of Cervical Cancer Cells (SiHa) via Altered Expression of p53, and E-cadherin/β-catenin Complex

It has been reported that metastasis-associated gene 1 （Mta1） is overexpressed in many malignant tumors with high metastatic potential. In addition, some studies indicated that MTA1 participated in invasion, metastasis, and survival of cancer cells by regulating cell migration, adhesion and proliferation. But the role of MTA1 is unclear in vitro in the development of cervical cancer cells. This study investigated whether and how MTA1 mediated cell proliferation, migration, invasion and adhesion in cervical cancer. MTA1 expression level was detected by Western blot in two cervical cancer cell lines of different invasion potentials. The effects of MTA1 expression on SiHa cell apoptosis, cycle, proliferation, migration, invasion and adhesion were tested by flow cytometry, MTT, wound-healing assay, Transwell assay and adhesion assay, respectively. The expression levels of p53, E-cadherin, and β-catenin activity were evaluated in untreated and treated cells. The results showed that MTA1 protein expression was significantly higher in SiHa than in HeLa, which was correlated well with the potential of migration and invasion in both cell lines. Furthermore, the cell invasion, migration and adhesion capabilities were decreased after inhibition of MTA1 expression mediated by Mta1-siRNA transfection in SiHa. However, no significant differences were found in cell apoptosis, cycle, and proliferation. In addition, E-cadherin and p53 protein levels were significantly up-regulated, while β-catenin was significantly down-regulated in SiHa transfected with the siRNA. These results demonstrated that MTA1 played an important role in the migration and invasion of cervical cancer cells. It was speculated that the decreased migration and invasion capability by inhibiting the MTA1 expression in the SiHa cell line may be mediated through the altered expression of p53, and E-cadherin/β-catenin complex. MTA1 could serve as a potential therapeutic target in cervical cancer.

Effect of siRNA Targeting MTA1 on Metastasis Malignant Phenotype of Ovarian Cancer A2780 Cells

Ovarian cancer is the fifth lethal gynecologic malignancy. Metastasis-associated gene 1 （MTA1） is overexpressed in many malignant tumors with high metastatic potential. This study investi- gated whether down-regulation of MTA1 expression by RNAi in A2780 ovarian cancer cells could affect proliferation, anoikis, migration, invasion and adhesion of the cells and to research the potential for MTA1 gene therapy of ovarian cancer. After transfection with effective Mtal gene siRNA, the effects on proliferation, anoikis, migration, invasion and adhesion of A2780 cells were tested by MTT assay, flow cytometry, wound-healing assay, Transwell assay and adhesion assay. Expression levels of PTEN, beta 1 integrin, MMP-9, phosphor-AKT （Ser473）, and total AKT activity were evaluated in control and transfected cells. The results showed that inhibition of MTA1 mediated by Mtal-siRNA transfection decreased the cell invasion, migration and adhesion, and induced the increased cell anoikis, but no significant difference was found in proliferation of A2780 cancer cells. In addition, beta 1 integrin, MMP-9, and phosphor-AKT protein levels were significantly down-regulated, while PTEN was significantly up-regulated. These results demonstrated that MTA1 played an important role in the cell metastasis in ovarian cancer. MTA1 could serve as another novel potential therapeutic target in ovarian cancer.

Detection of Copy Number Alteration of MTA1 in Human Breast Cancer

OBJECTIVE The purpose of our study was to investigate the expression level of MTA1 mRNA in breast cancer and its significance in relation to clinical pathology. METHODS The expression levels of MTA1 mRNA in tumor and in paired normal adjacent tissue of 56 cases with breast cancer were detected by fluorescent quantitative polymerase chain reaction. RESULTS The expression of MTA1 mRNA was detected in 47 tumor specimens of 56 breast cancer patients （83.9%） and was significantly higher than in the paired normal breast tissue. The over expressed MTA1 mRNA was significantly associated with pathologic stage （P = 0.029）, clinical grade （P = 0.035） and lymph node status （P = 0.001）. CONCLUSION The over expression of MTA1 mRNA may play a crucial role in the development of breast cancer. As the MTA1 was comparatively highly-expressed in breast cancer, it may become a new biomarker for the diagnosis and treatment of breast cancer in the future.

腹腔镜微创远端胃癌D2根治术治疗老年胃癌的效果及其对免疫功能、低氧诱导因子-1α和结肠癌转移相关基因1表达的影响

目的探讨腹腔镜微创远端胃癌D2根治术治疗老年胃癌的效果及其对免疫功能、低氧诱导因子-1α(HIF-1α)和结肠癌转移相关基因1(MACC1)表达的影响。方法选取2009年2月~2013年8月于四川省崇州市人民医院诊治的78例老年胃癌患者为研究对象,采用随机数字表法分为腹腔镜微创远端胃癌D2根治术组(微创组)和开腹远端胃癌D2根治术组(传统组),每组各39例,比较两组患者的近远期疗效、并发症情况、治疗前后免疫功能、HIF-1α和MACC1表达水平。结果微创组患者术中出血量少于传统组,胃肠道功能恢复时间短于传统组,并发症发生率低于传统组(P<0.05);两组患者手术时间和淋巴结清扫数目比较,差异无统计学意义(P>0.05)。两组患者平均生存时间、1年生存率、2年生存率和局部复发与转移率比较,差异无统计学意义(P>0.05)。两组患者治疗后IgM、IgG、CD4^+和CD4^+/CD8^+水平较治疗前升高,CD8^+、HIF-1α和MACC1水平较治疗前降低,且微创组上述指标的改善程度明显优于传统组(P<0.05);两组患者治疗前后Ig A和CD3^+水平比较,差异无统计学意义(P>0.05)。结论腹腔镜微创远端胃癌D2根治术可显著提高老年胃癌患者的近期临床疗效,改善患者免疫功能,抑制肿瘤相关基因HIF-1α和MACC1的表达。

Bioinformatic exploration of MTAl-regulated gene networks in colon cancer

Metastasis-associated gene 1 （MTA1） controls a series of biological processes in tumor progression. Tumor progression is a complex process regulated by a gene network. The global cancer gene regulatory network must be analyzed to determine the position of MTA1 in the molecular network and its cooperative genes by further exploring the biological functions of this gene. We used TCGA data sets and GeneCards database to screen MTA1- related genes. GO and KEGG pathway analyses were conducted with DAVID and gene network analysis via STRING and Cytoscape. Results showed that in the development of colon cancer, MTA1 is linked to certain signal pathways, such as Wnt/Notch/nucleotide excision repair pathways. The findings also suggested that MTA1 demonstrates the closest relationship in a coregulation process with the key molecules AKT1, EP300, CREBBP, SMARCA4, RHOA, and CAD. These results lead MTAI exploration to an in-depth investigation in different directions, such as Wnt, Notch, and DNA repair.

Screening of miRNAs associated with lymph node metastasis in Her-2-positive breast cancer and their relationship with prognosis

The aim of this study was to identify some biomarkers for predicting lymph node metastasis and prognosis of human epidermal growth factor receptor 2(Her-2)-positive breast cancer(BC). We analyzed correlations between micro RNAs(mi RNAs) and the prognosis of patients with BC based on data collected from The Cancer Genome Atlas(TCGA) database. The expression levels of mi R-455, mi R-143, and mi R-99 a were measured in clinical samples of Her-2-positive BC patients with different degrees of lymph node metastasis. We investigated the impacts of overexpressed mi R-455 on the proliferation and invasiveness of MDA-MB-453 cells and measured its effects on the expression of long non-coding RNA(lnc RNA) metastasis-associated lung adenocarcinoma transcript 1(MALAT1) by quantitative real-time polymerase chain reaction(q RT-PCR). The expression of mi R-455 was significantly and positively correlated to the prognosis and overall survival(OS) of the BC(P=0.028), according to TCGA information. The expression level of mi R-455 was positively correlated with OS and relapse-free survival(RFS) of patients with Her-2-positive BC, and was negatively correlated with the number of metastatic lymph nodes(P<0.05). Transwell assay suggested that MDA-MB-453 cells became much less invasive(P<0.01) after being transfected with mi R-455 mimics. During the q RT-PCR, the expression level of MALAT1 declined significantly after transfection(P<0.01). Overexpressed mi R-455 significantly inhibited the proliferation and migration of MDA-MB-453 cells and the expression of MALAT1. We conclude that mi R-455 may be a useful potential biomarker for forecasting lymph node metastasis and the prognosis of Her-2-positive BC patients. mi R-455 may play an important role in lymph node metastasis of BC by interacting with MALAT1.