Metastasis-associated In Colon Cancer-1 Overexpression Research Articles

Curcumin inhibits malignant behavior of colorectal cancer cells by regulating M2 polarization of tumor-associated macrophages and metastasis associated in colon cancer 1 (MACC1) expression.

The present study was to investigate the underlying mechanism of the antitumor effect of curcumin in colorectal cancer cells, focusing on the M2 polarization of tumor-associated macrophages (TAMs). The effect of curcumin on the malignant behavior of colorectal cancer cells was investigated by WST assay for cell growth, and Transwell assay for cell migration/invasion. THP-1 cells were differentiated into macrophages and coculture with colorectal cancer cells to study the influence of curcumin on M2 polarization, presenting as the levels of ARG1 mRNA, IL-10, and CD163-positive cells. GEO database was searched for the shared altered gene of curcumin in colorectal cells and human monocytes. Molecular docking was used to visualize the binding between curcumin and MACC1. Curcumin restricted the proliferation, apoptosis, and migration/invasion of HCT 116 and SW620 cells. Curcumin attenuated levels of the M2 macrophage markers, CD163 + cells, IL-10 secretion, and ARG1 mRNA. MACC1 was a target of curcumin in colorectal cancer cells, relating to macrophage. Rescue experiments showed that MACC1 overexpression can reverse the antitumor effect of curcumin in colorectal cancer cells and M2 polarization of TAMs. Curcumin's antiproliferative and anti-migratory effects in colorectal cancer cells may be mediated by MACC1 and inhibition of M2 polarization of TAMs.

MACC1 as a Potential Target for the Treatment and Prevention of Breast Cancer

Metastasis associated in colon cancer 1 (MACC1) is an oncogene first identified in colon cancer. MACC1 has been identified in more than 20 different types of solid cancers. It is a key prognostic biomarker in clinical practice and is involved in recurrence, metastasis, and survival in many types of human cancers. MACC1 is significantly associated with the primary tumor, lymph node metastasis, distant metastasis classification, and clinical staging in patients with breast cancer (BC), and MACC1 overexpression is associated with reduced recurrence-free survival (RFS) and worse overall survival (OS) in patients. In addition, MACC1 is involved in BC progression in multiple ways. MACC1 promotes the immune escape of BC cells by affecting the infiltration of immune cells in the tumor microenvironment. Since the FGD5AS1/miR-497/MACC1 axis inhibits the apoptotic pathway in radiation-resistant BC tissues and cell lines, the MACC1 gene may play an important role in BC resistance to radiation. Since MACC1 is involved in numerous biological processes inside and outside BC cells, it is a key player in the tumor microenvironment. Focusing on MACC1, this article briefly discusses its biological effects, emphasizes its molecular mechanisms and pathways of action, and describes its use in the treatment and prevention of breast cancer.

MACC1-Induced Collective Migration Is Promoted by Proliferation Rather Than Single Cell Biomechanics.

Simple SummaryHigh metastasis-associated in colon cancer 1 (MACC1) expression is associated with metastasis, tumor cell migration, and increased proliferation in colorectal cancer. Tumors with high MACC1 expression show a worse prognosis and higher invasion into neighboring structures. However, the mediation of the pro-migratory effects is still a matter of investigation. The aim of this study was to elucidate the impact of single cell biomechanics and proliferation on MACC1-dependent migration. We found that MACC1 expression associated with increased collective migration, caused by increased proliferation, and no changes in single cell biomechanics. Thus, targeting proliferation in high-MACC1-expressing tumors may offer additional effects on cell migration.Metastasis-associated in colon cancer 1 (MACC1) is a marker for metastasis, tumor cell migration, and increased proliferation in colorectal cancer (CRC). Tumors with high MACC1 expression show a worse prognosis and higher invasion into neighboring structures. Yet, many facets of the pro-migratory effects are not fully understood. Atomic force microscopy and single cell live imaging were used to quantify biomechanical and migratory properties in low- and high-MACC1-expressing CRC cells. Furthermore, collective migration and expansion of small, cohesive cell colonies were analyzed using live cell imaging and particle image velocimetry. Lastly, the impact of proliferation on collective migration was determined by inhibition of proliferation using mitomycin. MACC1 did not affect elasticity, cortex tension, and single cell migration of CRC cells but promoted collective migration and colony expansion in vitro. Measurements of the local velocities in the dense cell layers revealed proliferation events as regions of high local speeds. Inhibition of proliferation via mitomycin abrogated the MACC1-associated effects on the collective migration speeds. A simple simulation revealed that the expansion of cell clusters without proliferation appeared to be determined mostly by single cell properties. MACC1 overexpression does not influence single cell biomechanics and migration but only collective migration in a proliferation-dependent manner. Thus, targeting proliferation in high-MACC1-expressing tumors may offer additional effects on cell migration.

MACC1 Is Associated With Epithelial-Mesenchymal Transition and Can Predict Poor Prognosis in Nasopharyngeal Carcinoma.

BackgroundGiven the reported correlation between the oncogene metastasis-associated in colon cancer 1 (MACC1) and nasopharyngeal carcinoma (NPC), as well as between MACC1 and epithelial–mesenchymal transition (EMT), we speculated that EMT is a likely causative link between MACC1 expression and poor NPC prognosis. Thus, we aim to clarify the relationship between MACC1 and EMT in NPC prognosis.Material and MethodsWe performed immunohistochemical examination of tissue sections from 128 NPC patients that were divided into six groups corresponding to high and low protein expression of MACC1 and two EMT-related proteins, vimentin and E-cadherin, and Kaplan–Meier (KM) survival analyses were performed.ResultsKM survival analysis showed that upregulation of MACC1 and vimentin and downregulation of E-cadherin were significantly associated with reduced survival in NPC. Short hairpin RNA (shRNA) interference and immunoblotting in the NPC cell line HNE-1 led to increased E-cadherin but decreased vimentin levels. MACC1 overexpression was significantly correlated with poor 5-year overall survival, metastasis-free survival, and disease-free survival (P<0.05) but not with poor relapse-free survival (P>0.05). Univariate analyses revealed that MACC1, E-cadherin, and vimentin levels along with T and N tumor classifications and cancer staging are significant prognostic factors of NPC (P<0.05).ConclusionOur findings showed the association between MACC1 and EMT in NPC malignancy and support the role of MACC1 as a prognostic biomarker and molecular target for NPC treatment.

Circ_0006174 Accelerates Colorectal Cancer Progression Through Regulating miR-138-5p/MACC1 Axis.

BackgroundCircular RNAs (circRNAs) were reported to be involved in the progression of a variety of cancers, including colorectal cancer (CRC). However, the precise functions and mechanism of circRNAs in CRC have not been elucidated. This study aimed to investigate the effect and mechanism underlying circ_0006174 in CRC.MethodsThe expression of circ_0006174, microRNA (miR-138-5p) and metastasis associated in colon cancer 1 (MACC1) mRNA was detected by quantitative real-time polymerase chain reaction (RT-qPCR) assay. Western blot was employed to measure MACC1 protein expression. The effects of circ_0006174 knockdown, MACC1 overexpression or miR-138-5p inhibition on cell proliferation, migration, invasion, and apoptosis were assessed by cell counting kit 8 (CCK-8) assay, clone formation assay, transwell assay and flow cytometry assay, respectively. The interaction between miR-138-5p and circ_0006174 or MACC1 was confirmed by RNA pull down assay or dual-luciferase reporter assay. Xenograft tumor model in nude mice was used to verify the function of circ_0006174 in vivo.ResultsCirc_0006174 and MACC1 expression was highly expressed, while miR-138-5p expression was downregulated in CRC cells and tissues. Meanwhile, circ_0006174 functioned as a sponge of miR-138-5p to upregulate MACC1 expression. Furthermore, circ_0006174 knock down-mediated suppression on cell proliferation, migration and invasion, and promotion on cell apoptosis could be alleviated by MACC1 overexpression or miR-138-5p inhibition in CRC cells. Besides, circ_0006174 knockdown also inhibited CRC procession in vivo.ConclusionCirc_0006174 advanced CRC progression via sponging miR-138-5p to upregulate MACC1 expression, which may provide a promising molecular target for CRC treatment.

MACC1 Contributes to the Development of Osteosarcoma Through Regulation of the HGF/c-Met Pathway and Microtubule Stability.

Osteosarcoma (OS) is the most prevalent human bone malignancy, and presents a global annual morbidity of approximately five cases per million. Notably, precise and efficient targeted therapy has become the most promising strategy for the treatment of OS; however, there is still an urgent need for the identification of suitable therapeutic targets. Metastasis-associated in colon cancer 1 (MACC1) was first identified in colon tumors by differential display RT-PCR, and was shown to be involved in the regulation of colon tumor growth and metastasis through the hepatocyte growth factor (HGF)/c-Met signaling pathway. Additionally, MACC1 overexpression has been reported to induce the growth of several types of cancers, including glioblastoma multiforme and gastric cancer. However, whether MACC1 also plays a role in the progression of OS remains unclear. In this study, we found that MACC1 was highly expressed in human OS tissues, as well as in U-2OS and MG-63 cells, when compared with normal tissues and osteoblasts, respectively. Our data further indicated that MACC1 expression was correlated with several clinicopathological features of OS. Through in vitro assays, we found that MACC1 depletion markedly suppressed the proliferative ability of both OS cells and endothelial cells, and inhibited the angiogenic capacity of endothelial cells. Similarly, MACC1 depletion inhibited tumor growth, metastasis, and angiogenesis in mice. Mechanistically, we found that MACC1 could bind to the MET promoter, and enhanced the proliferation of both OS cells and endothelial cells through the HGF/c-Met signaling pathway. Furthermore, we show that MACC1 also promoted angiogenesis by regulating microtubule dynamics, thereby promoting the progression of OS. Our results indicate that MACC1 may be a new and promising therapeutic target for the treatment of OS.

MACC1 regulates PDL1 expression and tumor immunity through the c-Met/AKT/mTOR pathway in gastric cancer cells.

BackgroundImmunotherapy and its mechanisms are being studied in a wide variety of cancers. Programmed cell death ligand 1 (PDL1) is associated with immune evasion in numerous tumor types. Here, we aimed to assess the relationship between metastasis associated in colon cancer‐1 (MACC1) and PDL1 and examine their effects on gastric cancer (GC) tumor immunity.MethodsThe expression of MACC1, c‐Met, and PDL1 in human GC tissues was first assessed using quantitative RT‐PCR (qRT‐PCR) and immunohistochemistry. We then focused on the relationships among MACC1, c‐Met, and PDL1 using RT‐PCR and western blotting after cell transfection and inhibitor treatment in vitro and on the identification of their roles in immune killing in vitro and in vivo.ResultsWe found that expression of MACC1, c‐Met, and PDL1 was upregulated in human GC tissues, and there was a positive correlation between the expression levels. In addition, we found that ectopic expression of MACC1 (silencing and overexpression by transfection) resulted in corresponding changes in c‐Met and PDL1 expression levels, and c‐Met/AKT/mTOR pathway inhibitors (SU11274, MK2206, and rapamycin) blocked the regulation of PDL1 expression by MACC1. Furthermore, silencing of MACC1 led to an increase in antitumor and immune killing in vitro and in vivo, and overexpression of MACC1 resulted in a decrease in tumor immunity in vitro and in vivo.ConclusionsFrom these data, we infer that MACC1 regulates PDL1 expression and tumor immunity through the c‐Met/AKT/mTOR pathway in GC cells and suggest that MACC1 may be a therapeutic target for GC immunotherapy.

Clinicopathological and prognostic significance of metastasis-associated in colon cancer-1 in gastric cancer: A meta-analysis.

The gene metastasis-associated in colon cancer-1 (MACC1) has been reported to be overexpressed in diverse human malignancies, and an increasing amount of evidence suggests that its overexpression is associated with the development and progression of many human tumors. However, the prognostic and clinicopathological value of MACC1 in gastric cancer remains inconclusive. Therefore, we conducted this meta-analysis to investigate the effect of positive MACC1 expression on clinicopathological features and survival outcomes in gastric cancer. Medline, Web of Science, and EMBASE databases were searched for relevant articles published up to 10 April 2018. The correlation of MACC1 expression levels with overall survival and clinicopathological features was analyzed. In this meta-analysis, nine studies with a total of 2103 gastric cancer patients were included. Our results showed that high expression of MACC1 was significantly related to a poor overall survival. Moreover, our meta-analysis showed that MACC1 overexpression was significantly linked to distant metastasis and vascular invasion. There were no significant correlations between positive MACC1 expression and gender, localization, tumor-node-metastasis (TNM) stage, tumor extent (T stage) and lymph node involvement (N stage). MACC1 expression levels can serve as a novel prognostic factor in gastric cancer patients.

Cisplatin resistance in lung cancer is mediated by MACC1 expression through PI3K/AKT signaling pathway activation.

One of the major obstacles hindering the treatment of lung cancer (LC) is chemoresistance; however, its mechanism remains unclear. The overexpression of the metastasis-associated in colon cancer 1 (MACC1) gene has been demonstrated to reverse chemoresistance. In the current study, the expression of MACC1 in LC cells with cisplatin resistance (Cis-Re) was investigated. Cisplatin-resistant cell sublines (A549/CR and H446/CR) were induced by stepwise escalation of cisplatin exposure. MTS and flow cytometry assays were performed to measure cell proliferation and apoptosis, respectively. Western blot analysis and qRT-PCR assays were performed to determine the changes in signaling pathway-related protein and mRNA levels, respectively. A nude mouse xenograft model was used for in vivo experiments. Our results showed that MACC1 expression was increased in the cisplatin-resistant A549/CR and H446/CR cell lines, and the resistance was reversed with a decrease of MACC1 expression. MACC1 overexpression triggered an increase of Cis-Re, which was contrary to the effect of MACC1 down-regulation. In addition, the effect of MACC1 on Cis-Re was blocked by the inhibition of the PI3K/AKT pathway, and treatment with both cisplatin and a PI3K/AKT inhibitor effectively inhibited tumor growth in xenografts with MACC1 overexpression. In conclusion, our results revealed that MACC1 increased Cis-Re partially via the PI3K/AKT signaling pathway, suggesting that MACC1 could serve as a potential target to overcome Cis-Re. Furthermore, combination therapy could alleviate Cis-Re resulted from MACC1 overexpression in patients with LC.

The role of metastasis-associated in colon cancer 1 (MACC1) in endometrial carcinoma tumorigenesis and progression.

Metastasis-associated in colon cancer-1 (MACC1), has recently been identified as a key regulator in the progression of many cancers. However, its role in endometrial carcinoma (EC) remains unknown. MACC1 expression was determined in EC and normal endometrial tissues by immunohistochemistry. EC cell phenotypes and related molecules were examined after MACC1 downregulation by Small interfering RNA (siRNA) or microRNA (miRNA) transfection. We found that MACC1 was highly expressed in EC tissues than normal samples, and was significantly different in FIGO staging (I and II vs. III and IV), the depth of myometrial infiltration (<1/2 vs. ≥1/2), lymph nodes metastasis (negative vs. positive), besides, MACC1 overexpression was correlated with lower cumulative and relapse-free survival rate. MACC1 downregulation by siRNA transfection significantly induced G1 phrase arrest, suppressed EC cell proliferation, migration, and invasion. In addition, MACC1 downregulation also reduced expression of Cyclin D1 and Cyclin-dependent Kinase 2 (CDK2), N-cadherin (N-Ca), α-SMA, matrix metalloproteinase 2 (MMP2), and MMP9, but increased expression of E-cadherin (E-Ca). Bioinformatic predictions and dual-luciferase reporter assays indicate that MACC1 is a possible target of miR-23b. MiR-23b overexpression reduced MACC1 expression in vitro and induced G1 phrase arrest, suppressed cell proliferation, migration, and invasion. MiR-23b transfection also reduced Cyclin D1 and CDK2, N-Ca, α-SMA, MMP2, MMP9 expression, but increased E-Ca expression. Furthermore, the nude mouse xenograft assay showed that miR-23b overexpression suppressed tumour growth through downregulating MACC1 expression. Taken together, our results demonstrate for the first time that MACC1 may be a new and important diagnosis and therapeutic target of endometrial carcinoma.

Clinicopathological and prognostic significance of metastasis-associated in colon cancer-1 (MACC1) overexpression in colorectal cancer: a meta-analysis.

Metastasis-associated in colon cancer-1 (MACC1) has been reported to be overexpressed in diverse human malignancies, and the increasing amount of evidences suggest that its overexpression is associated with the development and progression of many human tumors. However, the prognostic and clinicopathological value of MACC1 in colorectal cancer remains inconclusive. Therefore, we conducted this meta-analysis to investigate the effect of MACC1 overexpression on clinicopathological features and survival outcomes in colorectal cancer. PubMed, CNKI, and Wanfang databases were searched for relevant articles published update to December 2015. Correlation of MACC1 expression level with overall survival (OS), disease-free survival (DFS), and clinicopathological features were analyzed. In this meta-analysis, fifteen studies with a total of 2,161 colorectal cancer patients were included. Our results showed that MACC1 overexpression was significantly associated with poorer OS and DFS. Moreover, MACC1 overexpression was significantly associated with gender, localization, TNM stage, T stage, and N stage. Together, our meta-analysis showed that MACC1 overexpression was significantly associated with poor survival rates, regional invasion and lymph-node metastasis. MACC1 expression level can serve as a novel prognostic factor in colorectal cancer patients.

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 tumor 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 epithelial-to-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.

Abstract P6-01-20: A role of MACC1 expression and its regulation of the HGF/c-Met pathway in breast cancer

Abstract Background The newly identified gene, metastasis-associated in colon cancer 1 (MACC1), is suggested to be a transcriptional regulator of the receptor tyrosine kinase gene c-Met, leading to cancer progression and metastasis in colorectal cancer. Also in breast cancer, aberrant hepatocyte growth factor (HGF) / c-Met signaling has been shown to contribute to worse prognosis and confer resistance to endocrine therapy or trastuzumab treatment, however, little is known of the role of MACC1. Here, we report its impact on the survival for breast cancer patients and the biological function in the cell lines. Methods A total of 300 breast cancer patients who received both surgery and adjuvant treatment at Kumamoto University Hospital between 2001 and 2009 were selected. We analyzed expressions of MACC1 by reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) to evaluate the associations of its expression with breast cancer survival. In an in vitro study, the expressions of MACC1 were examined by Western blotting in breast and colorectal cancer cell lines. After transfection with a MACC1-harboing plasmid, we evaluated the activities of cMet protein and cell motility and proliferation. Further, the binding ability of MACC1 to the cMet promoter was evaluated using chromatin immunoprecipitation (ChIP) assay. Results In survival analyses, reduced MACC1 expressions were associated with patient mortality. Cox proportional hazards model showed that MACC1 mRNA (HR = 0.25, P = 0.001), MACC1 protein (HR = 0.37, P = 0.016), as well as axillary nodal status and estrogen receptor status, were independent predictors of mortality. No significant correlations between MACC1 expression and other clinicopathological factors were found. We found no strong positive correlation between MACC1 protein and c-Met mRNA expression with a Spearman’s coefficient of 0.16 (P = 0.0067). In the cell lines tested, MACC1 expression was much higher in colorectal cancer cells (DLD-1) than breast cancer cells (MCF7 and MDA-MB-231). To investigate the impact of MACC1 on the biological function of the cells, we transfected with MACC1 in breast cancer and colorectal cancer cells (SW480). MACC1 overexpression did not induce cMet expression in MCF7, whereas the corresponding cMet expression was upregulated in SW480 cells. Further, SW480 cells transfected with MACC1 showed enhanced migratory ability, whereas in MDA-MB-231 cells, transfection of MACC1 had no impact on this ability. In ChIP assay, the binding of MACC1 to the cMet promoter region was suggested in SW480 cells, but not in MCF7 cells. Conclusions Our findings provide some novel insights into the role of MACC1 for breast cancer, indicating that it plays different roles in breast cancer and in several other cancers. The biological mechanism of MACC1 which underlies improvement of breast cancer prognosis remains unelucidated. There is possibility that MACC1 does not act as the exclusive master regulator of the HGF/c-Met signaling involved in disease progression in breast cancer. Further studies to validate our results are needed. Citation Format: Aiko Sueta, Yutaka Yamamoto, Mitsuhiro Hayashi, Takashi Takeshita, Mutsuko Ibusuki, Hirotaka Iwase. A role of MACC1 expression and its regulation of the HGF/c-Met pathway in breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-01-20.

Overexpression of MACC1 and the association with hepatocyte growth factor/c-Met in epithelial ovarian cancer.

Metastasis-associated in colon cancer-1 (MACC1) is a gene that has been newly identified by a genome-wide search for differentially expressed genes in human colon cancer tissues, metastases and normal tissues. MACC1 exerts an important role in colon cancer metastasis through upregulation of the c-Met proto-oncogene. The tyrosine kinase receptor encoded by the c-Met oncogene exhibits the unusual property of mediating the invasive growth of epithelial cells upon binding with the hepatocyte growth factor (HGF). MACC1 has been investigated with regard to colon carcinoma and MACC1 expression is associated with metastasis in various types of human cancer. However, the value of MACC1 as a potential biomarker for ovarian cancer remains unknown, although the c-Met/HGF receptor has been shown to be overexpressed in epithelial ovarian cancer tissues. To investigate the role of MACC1 in epithelial ovarian tumors, the expression levels of MACC1 mRNA in ovarian tumor specimens were analyzed together with the prognostic significance. MACC1 protein expression was also detected in the epithelial ovarian tissue specimens, and the effects of MACC1 overexpression on ovarian cancer migration, invasion and prognosis were evaluated. Due to the close association between MACC1 and c-Met expression levels in colon cancer, the expression levels of HGF/c-Met in the ovarian specimens were also examined to determine whether such a correlation is also present in epithelial ovarian cancer. A total of 92 epithelial ovarian tissue samples were used to assess the expression levels of MACC1 mRNA and protein using reverse transcription-polymerase chain reaction and immunohistochemical methods, respectively. The serum levels of MACC1 protein expression in patients with epithelial ovarian cancer were detected by enzyme-linked immunosorbent assay. The results indicated that MACC1 may be important in the malignant progression of epithelial ovarian tumors, in particular for early stage patients. Thus, MACC1 may become a predictor of prognosis and a therapeutic target in the treatment of ovarian tumors. The combined detection of MACC1 and HGF/c-Met is therefore important in assessing the prognosis of patients with malignant epithelial ovarian tumors.

MACC1 overexpression and survival in solid tumors: a meta-analysis

Metastasis associated in colon cancer-1 (MACC1) is a newly identified oncogene, and increasing evidence has suggested that its overexpression is associated with the development and progression in many tumors. Here, we perform a meta-analysis to assess the relationship between MACC1 overexpression and survival in solid tumors. Eligible studies were searched in Embase, PubMed, and Web of Science databases up to May 2014. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to estimate the impact of MACC1 overexpression on survival using a random-effect model. A total of 20 eligible studies dealing with various tumors were included in the analysis: 17 were dealing with overall survival (OS), 7 were with relapse-free survival (RFS), and 3 were with disease-free survival (DFS). Combined results suggested a strong link between the high MACC1 expression and the poor overall survival (HR 2.11, 95% CI 1.59-2.80, P < 0.001). For relapse-free survival, overexpressed MACC1 was also a significant predictor, with a combined HR of 2.22 (95% CI 1.80-2.74, P < 0.001). Data from the three studies were combined to show that MACC1 overexpression had also an unfavorable impact on disease-free survival (HR 2.94, 95% CI 1.60-5.38, P < 0.001). Publication bias was not significant. The present meta-analysis showed that overexpression of MACC1 was significantly associated with poorer survival in solid tumors.

MACC1 promotes carcinogenesis of colorectal cancer via β-catenin signaling pathway.

Here we confirmed that metastasis-associated in colon cancer 1 (MACC1) and β-catenin expression were higher in colorectal cancer (CRC) cells and tissues than those in normal colonic epithelial cell line and adjacent non-tumour colorectal mucosa (ANM) tissues, respectively. MACC1 expression was significantly related to histological differentiation (p<0.001), UICC stage (p=0.029), T classification (p=0.017), and N classification (p=0.023). Cox regression analysis demonstrated that high MACC1/abnormal β-catenin expression was the strongest independent prognostic indicator for reduced overall survival in CRC patients. Significant positive correlation between MACC1 expression and abnormal β-catenin expression was found in CRC tissues. MACC1 knockdown dramatically inhibited cellular proliferation, migration, invasion, colony formation, and tumorigenesis, both in vitro and in vivo, but induced apoptosis in CRC cells. Further MACC1 over-expression increased Met, β-catenin, and its downstream genes including c-Myc, cyclin D1, and MMP9 expression, and its upstream gene phos-GSK3β (Ser9) expression. In addition, MACC1 increased vimentin and suppressed E-cadherin in HCT116 cells. Silencing of MACC1 reversed all these changes. Our results firstly suggest that MACC1 plays an important role in carcinogenesis and progression of CRC through β-catenin signaling pathway and mesenchymal-epithelial transition.

Expression of MACC1 and MET in Inflammatory Bowel Disease-associated Colonic Neoplasia

Metastasis-associated in colon cancer-1 (MACC1), a newly identified regulator of HGF-MET signaling, may participate into the key steps of sporadic colorectal adenocarcinoma development. Given there are many pathogenetic distinctions between colitis-associated colorectal cancer (CAC) and sporadic colorectal adenocarcinomas, the potential roles of MACC1 in CAC carcinogenesis remain unknown. For the first time, we evaluated the expressions of MACC1 and MET in IBD-associated colitis, dysplasia, and adenocarcinoma. Expression was investigated by immunohistochemistry in tissue microarrays consisting of 13 normal colon, 11 active colitis, 9 dysplasia, 51 conventional CAC, 5 mucinous adenocarcinoma, and 1 signet ring cell adenocarcinoma specimens. The expression level of MACC1 or MET was evaluated with H-score system. MACC1 expression was significantly higher in IBD-associated dysplasia than that in corresponding inflammatory or normal colonic tissue, and its level was further elevated from dysplasia to conventional CAC. Higher MACC1 expression was seen in a patient with CAC who had multifocal dysplasia or synchronous carcinoma. MACC1 overexpression (H-score >100) was seen in 67% of conventional CAC but in 0% of dysplasia and 0% of inflammation or normal colon. There was no difference of MACC1 expression found among well, moderately and poorly differentiated CAC. MET expressions in inflammation, dysplasia, and conventional CAC were statistically similar. No parallel expression of MACC1 and MET was detected in this study. MACC1 and MET expression was not increased in mucinous or signet ring cell carcinoma, 2 distinct variants of CAC. Stepwise increase of MACC1 expression from IBD-associated colitis to dysplasia to adenocarcinoma suggests that MACC1 is strongly associated with conventional CAC tumorigenesis in a manner independent of MET. MACC1 may serve as a potential marker for early diagnosis of conventional CAC.

Effects of MACC1 siRNA on biological behaviors of HeLa

Metastasis-associated in colon cancer 1 (MACC1) has been shown to play a critical role in several types of cancer. The purposes of this study were to evaluate MACC1 expression in cervical cancer and determine role of MACC1 small interference RNA (siRNA) in the growth and progression of cervical cancer. Immunohistochemical analysis of MACC1 expression was performed in different cervical lesion tissues. siRNA knockdown of MACC1 was performed. Cytoskeletal staining, RT-PCR, Western blot technology, transwell migration, MTT, and flow cytometry were used for identification of the functional roles of MACC1 siRNA in HeLa cells. Immunohistochemistry demonstrated that MACC1 overexpression was detected in cervical cancer tissues. MACC1 siRNA transfection remarkably affected HeLa cell biological behaviors. Expression of MACC1 in HeLa cells was significantly down-regulated by MACC1 siRNA. In addition, knockdown of MACC1 in HeLa cells caused a significant decrease in cell proliferation or migration, and increased cell apoptosis rate. Flow cytometry showed that MACC1 siRNA may inhibit cell proliferation by interfering with cell mitosis and cell cycle progression. These results suggest that MACC1 is a novel biomarker for cervical cancer diagnosis and a target for therapeutic interventions. Decreasing MACC1 expression by siRNA may prove to be an effective genetic therapy strategy.

MACC1 overexpression predicts a poor prognosis for non-small cell lung cancer

The expression of metastasis-associated in colon cancer-1 (MACC1) in non-small cell lung cancer (NSCLC) and its association with pathological characteristics and prognosis for NSCLC patients were investigated retrospectively. The expression of MACC1 was evaluated through immunohistochemical staining of tissue microarrays from 180 samples of resected lung cancer tissues and adjacent normal lung tissues. MACC1 protein and mRNA expression were also examined from lung cancer cell lines with different metastatic potentials, 28 pairs of samples of resected fresh non-small cell lung cancer tissues, and adjacent normal lung tissues. Immunohistochemical staining of tissue microarrays showed that MACC1 was located in the cytoplasm. In addition, the expression of MACC1 protein in NSCLC was significantly higher compared to adjacent normal tissues (P < 0.001). The expression of MACC1 was positively associated with differentiation grade (P = 0.020), postoperative pathological TNM stage (P = 0.033), and lymph node metastasis (P = 0.028). Disease-free survival (DFS) and overall survival (OS) for the high MACC1 expression group were lower than the low expression group; univariate and multivariate regression analyses showed that MACC1 was an independent prognostic indicator for DFS (HR 3.124, P = 0.01) and OS (HR 2.905, P = 0.01) in NSCLC patients. The expression of MACC1 protein and mRNA was also upregulated in highly metastatic human lung cancer. In conclusion, the overexpression of MACC1 protein and mRNA may represent a potentially useful biomarker for the prognosis of NSCLC patients and might be involved in progression of NSCLC.

Overexpression of MACC1 protein and its clinical implications in patients with glioma

Metastasis associated in colon cancer 1 (MACC1) has been regarded as a novel potential therapeutic target for multiple cancers. However, the impact of MACC1 in glioma remains unclear. The aim of this study was to analyze the correlation of MACC1 expression with the clinicopathological features of glioma. MACC1 mRNA and protein expression levels in human glioma tissues were detected by quantitative real-time polymerase chain reaction and immunohistochemistry assays, respectively. MACC1 mRNA and protein expression were both significantly higher in glioma tissues than in corresponding noncancerous brain tissues (both P < 0.001). In addition, statistical analysis suggested that high MACC1 expression was significantly correlated with advanced pathological grade (P = 0.004) and that patients with high expression of MACC1 protein exhibited a poorer prognosis than those with low MACC1 expression. Furthermore, Cox multivariate analysis showed that MACC1 overexpression was an independent prognostic factor for predicting the overall survival of glioma patients. In conclusion, expression of MACC1 in glioma could be adopted as a candidate biomarker for the diagnosis of clinical stage and for assessing prognosis, indicating for the first time that MACC1 may play an important role in the tumor development and progression in glioma. MACC1 might be considered as a novel therapeutic target against this cancer.