Tumor Progression In Colorectal Cancer Research Articles

Construction of an miRNA‑gene regulatory network in colorectal cancer through integrated analysis of mRNA and miRNA microarrays.

The aim of the present study was to identify potential biomarkers associated with colorectal cancer (CRC). The GSE32323 and GSE53592 mRNA and microRNA (miRNA) expression profiles were selected from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) in CRC tissue samples compared with surrounding control tissue samples (DEGs‑CC), and DEGs in cells treated with 5‑aza‑2'‑deoxycitidine compared with untreated cells (DEGs‑TC) were identified with the Limma package. The Database for Annotation, Visualization and Integrated Discovery was used to conduct the functional and pathways enrichment analysis. Differential co‑regulation networks were constructed using the DCGL package of R. The targets of DEMs were identified using TargetScan. The overlaps between DEGs and the targets were selected. The miRNA‑gene regulatory network of the overlaps was established. There were 145DEMs, and 1,284DEGs in DEGs‑CC, and 101 DEGs in DEGs‑TC. DEGs‑CC were enriched in 196 Gene Ontology (GO) terms and 23Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. DEGs‑TC were enriched in 46GO terms and two KEGG pathways. A differential co‑regulation network of the DEGs and a miRNA‑gene regulatory network between DEMs and overlapped DEGs were respectively constructed. miR‑124‑3p, miR‑145‑5p and miR‑320a may be critical in CRC, and serum/glucocorticoid regulated kinase 1 and SRY‑box9 may be potential biomarkers for CRC tumor progression.

The Dual Role of MicroRNAs in Colorectal Cancer Progression

Colorectal cancer (CRC) is responsible for one of the major cancer incidence and mortality worldwide. It is well known that MicroRNAs (miRNAs) play vital roles in maintaining the cell development and other physiological processes, as well as, the aberrant expression of numerous miRNAs involved in CRC progression. MiRNAs are a class of small, endogenous, non-coding, single-stranded RNAs that bind to the 3’-untranslated region (3′-UTR) complementary sequences of their target mRNA, resulting in mRNA degradation or inhibition of its translation as a post-transcriptional regulators. Moreover, miRNAs also can target the long non-coding RNA (lncRNA) to regulate the expression of its target genes involved in proliferation and metastasis of CRC. The functions of these dysregulated miRNAs appear to be context specific, with evidence of having a dual role in both oncogenes and tumor suppression depending on the cellular environment in which they are expressed. Therefore, the unique expression profiles of miRNAs relate to the diagnosis, prognosis, and therapeutic outcome in CRC. In this review, we focused on several oncogenic and tumor-suppressive miRNAs specific to CRC, and assess their functions to uncover the molecular mechanisms of tumor initiation and progression in CRC. These data promised that miRNAs can be used as early detection biomarkers and potential therapeutic target in CRC patients.

RAC1-GTP promotes epithelial-mesenchymal transition and invasion of colorectal cancer by activation of STAT3

Epithelial-mesenchymal transition (EMT) plays a critical role in initiating tumor invasion and metastasis of colorectal cancer (CRC), although the underlying mechanisms remain to be clarified. Herein, we demonstrate that the active form of Rac family small GTPase 1 (RAC1-GTP) is overexpressed in CRCs and promotes the EMT-mediated invasion of CRC cells through activation of the signal transducers and activators of transcription 3 (STAT3) pathway. Increased expression of RAC1-GTP in CRC tissues was positively correlated with the TNM stages of CRCs and indicated poor prognosis of CRC patients. Targeting RAC1-GTP activity by its specific inhibitor NSC23766 markedly suppressed the migration and invasion of CRC cells. Mechanistically, RAC1-GTP directly interacted with STAT3 to promote STAT3 phosphorylation, thus promoted EMT of CRC cells. Enforced expression of constitutively activated STAT3 (STAT3-C) abrogated the suppressive effect of RAC1-GTP disruption on the migration and invasion of CRC cells. Importantly, NSC23766 disrupted EMT in CRC cells and significantly diminished growth of CRC xenografts. Taken together, our data indicate that RAC1-GTP is an important player in EMT-mediated tumor invasion and a potential therapeutic target for CRCs.In this study the authors show that Rac family small GTPase 1 (RAC1-GTP) is overexpressed in colorectal cancer (CRC) and promotes epithelial-mesenchymal transition-mediated invasion of CRC cells through activation of the STAT3 pathway. Overexpression of RAC1-GTP in CRCs correlates with tumor progression and recurrence of CRCs, and predicts poor prognosis of CRC patients.

A novel role for estrogen-induced signaling in the colorectal cancer gender bias.

Colorectal cancer (CRC) is a malignancy whose incidence is increasing globally, and there is a gender difference in the increasing risk. Evidence from hormone replacement therapy studies points to a role for circulating estrogens in suppressing the development of CRC. Estrogen receptor-β has been identified as a tumor suppressor, but other actions of estrogen may also contribute to the difference in CRC incidence between men and women. The KCNQ1/KCNE3 potassium channel is regulated by estrogen in order to modulate chloride secretion during the menstrual cycle; the effect of estrogen on the colon is to promote fluid conservation during the implantation window. KCNQ1 is also a tumor suppressor in CRC, and its sustained expression has been linked to suppression of the Wnt/β-catenin signaling pathway that contributes to CRC tumor progression. KCNQ1 regulation may represent a link between the normal physiological actions of estrogen in the colon and the hormone's apparent tumor-suppressive effects in CRC development.

Long non‑coding RNA 00152 functions as a competing endogenous RNA to regulate NRP1 expression by sponging with miRNA‑206 in colorectal cancer.

Colorectal cancer (CRC) is the third most common type of cancer; however, the molecular mechanisms underlying colorectal tumor metastasis and growth remain elusive. Recently, accumulating evidence has indicated that long non‑coding RNAs (lncRNAs) play a critical role in CRC progression and metastasis; however, the biological role and clinical significance of lncRNA 00152 (lnc00152) in CRC remains largely unknown. Thus, in this study, lnc00152 expression was measured in 80human CRC tissue samples, 40non‑cancerous tissue samples, and 3CRC cell lines (SW480, SW620 and LoVo) using RT‑qPCR. We examined the effects of lnc00152 on CRC cells following transfection with lnc00152 overexpression plasmid or respective siRNA invitro and invivo. Luciferase assays revealed the mechanism driving competitive endogenous RNA (ceRNA). We identified that lnc00152 was aberrantly overexpressed in colorectal tumors and cancer cells and that lnc00152 was modulated by miRNA‑206. lnc00152 overexpression enhanced the proliferative and invasive ability of CRC cells invitro, promoted tumor growth invivo, and was associated with the shorter overall survival of patients with CRC. In addition, lnc00152 overexpression promoted epithelial-mesenchymal transition(EMT) and increased neuropilin‑1 (NRP1) expression in the CRC cells. By contrast, lnc00152 silencing exerted a counteractive effect. Collectively, these findings demonstrate the critical role of lnc00152 in tumor growth and progression in CRC, and identify a novel therapeutic target associated with CRC development and progression.

Sorting nexin 10 controls mTOR activation through regulating amino-acid metabolism in colorectal cancer

Amino-acid metabolism plays a vital role in mammalian target of rapamycin (mTOR) signaling, which is the pivot in colorectal cancer (CRC). Upregulated chaperone-mediated autophagy (CMA) activity contributes to the regulation of metabolism in cancer cells. Previously, we found that sorting nexin 10 (SNX10) is a critical regulator in CMA activation. Here we investigated the role of SNX10 in regulating amino-acid metabolism and mTOR signaling pathway activation, as well as the impact on the tumor progression of mouse CRC. Our results showed that SNX10 deficiency promoted colorectal tumorigenesis in male FVB mice and CRC cell proliferation and survival. Metabolic pathway analysis of gas chromatography–mass spectrometry (GC-MS) data revealed unique changes of amino-acid metabolism by SNX10 deficiency. In HCT116 cells, SNX10 knockout resulted in the increase of CMA and mTOR activation, which could be abolished by chloroquine treatment or reversed by SNX10 overexpression. By small RNA interference (siRNA), we found that the activation of mTOR was dependent on lysosomal-associated membrane protein type-2A (LAMP-2A), which is a limiting factor of CMA. Similar results were also found in Caco-2 and SW480 cells. Ultra-high-performance liquid chromatography–quadrupole time of flight (UHPLC-QTOF) and GC-MS-based untargeted metabolomics revealed that 10 amino-acid metabolism in SNX10-deficient cells were significantly upregulated, which could be restored by LAMP-2A siRNA. All of these amino acids were previously reported to be involved in mTOR activation. In conclusion, this work revealed that SNX10 controls mTOR activation through regulating CMA-dependent amino-acid metabolism, which provides potential target and strategy for treating CRC.

High NUCB2 expression level is associated with metastasis and may promote tumor progression in colorectal cancer.

Nucleobindin 2 (NUCB2) is mainly expressed in the hypothalamic nuclei and has a proven role in energy homeostasis. It has also been recently reported to have a key role in tumor progression. However, the clinical significance of NUCB2 in colorectal cancer (CRC) remains unknown. In the present study, the level of NUCB2 mRNA was quantified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in 34 paired fresh tissues from patients with CRC. RT-qPCR was followed by immunohistochemical (IHC) staining of NUCB2 protein in tissue microarrays of 251 samples to evaluate the clinical significance of NUCB2 in CRC. The RT-qPCR indicated an upregulation of NUCB2 mRNA in CRC tissues compared with normal tissues (P=0.027). IHC staining indicated a positive association between elevated NUCB2 expression and lymph node metastasis or tumor-node-metastasis (TNM) stage. Patients with CRC and lymph node metastasis demonstrated a higher expression of NUCB2 (49.5%, 50/101) compared with those without lymph node metastasis (36.7%, 55/150; P=0.043). Furthermore, NUCB2 expression was also higher in patients with CRC and TNM stage III–IV compared with those with TNM stage I–II (50.9% vs. 35.0%; P=0.011). However, Kaplan-Meier analysis indicated no significant association between NUCB2 expression and disease-free survival of patients. Additionally, multivariate analysis did not identify the upregulation of NUCB2 as an independent prognostic predictor in patients with CRC (P=0.755). In conclusion, the present study demonstrated that upregulation of NUCB2 is significantly associated with CRC metastasis, indicating that NUCB2 may be a cancer-associated oncogene associated with the aggressive progression of CRC.

The downregulation of Rap1 GTPase-activating protein is associated with a poor prognosis in colorectal cancer and may impact on tumor progression.

Rap1 GTPase-activating protein (Rap1GAP) has been reported to serve an important role in various types of cancer by specific stimulation as a negative regulator of Rap1 activity. However, the role of Rap1GAP in colorectal cancer (CRC) has yet to be fully elucidated. The aim of the present study was to investigate the expression of Rap1GAP in CRC tissues and to elucidate its clinical significance. The expression of Rap1GAP, matrix metallopeptidase 9 (MMP-9) and E-cadherin in 227 CRC tissues and paired para-carcinoma tissues was detected by immunohistochemistry. Associations between Rap1GAP expression and clinicopathological characteristics, and between Rap1GAP expression and prognostic value (OS + DFS) in CRC were investigated. Furthermore, associations between Rap1GAP expression and MMP-9 expression, and between Rap1GAP expression and E-cadherin expression were also investigated. Rap1GAP expression was markedly downregulated in CRC tissues compared with para-carcinoma tissues. Decreased expression of Rap1GAP was significantly associated with depth of invasion, lymph node metastasis, advanced Tumor-Node-Metastasis stage and a poor prognosis in patients with CRC following surgery. Furthermore, univariate and multivariate analyses revealed that Rap1GAP was an independent poor prognostic factor for disease-free survival and overall survival. In addition, Rap1GAP expression was negatively associated with MMP-9 and positively associated with E-cadherin in 227 CRC samples. In brief, the results of the present study suggested that Rap1GAP may be involved in tumor progression in CRC and may serve as a potential target for prognostic prediction of patients with CRC.

SP1 upregulated FoxO3a promotes tumor progression in colorectal cancer.

FoxO transcription factors are important regulators of cell survival in response to a variety of stress stimuli and play vital functions in tumor progression. However, the functions and underlying regulators of FoxO3a in colorectal cancer (CRC) have not been fully elucidated. The aim of the current study was to identify the functions of FoxO3a in CRC and characterize the transcription elements within the promoter region of FoxO3a. The expression of FoxO3a was upregulated in response to hypoxic and oxidative stress stimuli. Furthermore, knockdown of FoxO3a significantly reduced cell proliferation and migration ability, while it promoted the response to cetuximab treatment. In addition, it was revealed that knockdown of FoxO3a reduced tumor progression invivo. A mechanistic study found that plenty of putative SP1 sites were identified in the FoxO3a promoter. Luciferase reporter assay revealed that a region corresponding to the SP1 binding sites located between ‑2,000 and ‑1,037bp of FoxO3a promoter was essential for the transcriptional activity. Co-transfection of a SP1 expression vector with the reporter constructs markedly increased luciferase activity. Collectively, these results indicated that SP1‑dependent promoter elements drive FoxO3a gene transcription in colorectal CRC, and indicated that SP1 upregulated FoxO3a is critical for CRC progression.

Expression of miR-200c and its clinicopathological significance in patients with colorectal cancer

MicroRNA-200c (miR-200c) is known to play a pivotal role in the regulation of epithelial-to-mesenchymal and mesenchymal-to-epithelial transition processes. However, the biological function of miR-200c in human carcinogenesis remains controversial. We examined the association of miR-200c expression with various clinicopathological factors, including KRAS mutation status and survival, in patients with colorectal cancer (CRC). The expression level of miR-200c was evaluated in 109 paired CRC and normal tissue samples using quantitative reverse transcription polymerase chain reaction. The KRAS mutation status of the CRC samples was determined using the PNAClamp™ KRAS Mutation Detection kit. Compared with the normal tissue group, miR-200c expression was significantly upregulated in the CRCs (P < .001). The expression of miR-200c was increased in CRCs with higher grade (P = .009), advanced stage (P = .042), and lymphovascular invasion (P = .003). Thirty-one CRCs (28.4%) had KRAS mutations in codon 12 or 13. CRCs with KRAS mutations had significantly higher miR-200c expression than CRCs with wild-type KRAS (P = .003). In survival analysis, high miR-200c expression was correlated with worse overall survival (P = .017) and recurrence-free survival (P = .048). Our results indicate that miR-200c is involved in tumor progression and aggressiveness in CRCs, and this oncogenic role of miR-200c may be triggered by activation of the KRAS signaling pathway.

The gain-of-function mutation E76K in SHP2 promotes CAC tumorigenesis and induces EMT via the Wnt/β-catenin signaling pathway.

SHP2 is encoded by the protein tyrosine phosphatase 11 (Ptpn11) gene. Several gain-of-function (GOF) mutations in Ptpn11 have been identified in human hematopoietic malignancies and solid tumors. In addition, the mutation rate for SHP2 is the highest for colorectal cancer (CRC) among solid tumors. The E76K GOF mutation is the most common and active SHP2 mutation; however, the pathogenic effects and function of this mutation in CRC tumor progression have not been well characterized. The Wnt/β-catenin (CTNNB1) signaling pathway is crucial for CRC, and excessive activation of this pathway has been observed in several tumors. We used Ptpn11E76K conditional knock-in mice to study this GOF mutation in colitis-associated CRC (CAC) and used the CRC cell lines HT29 and HCT116 to determine the relationship between SHP2 and Wnt/β-catenin signaling. Ptpn11E76K conditional knock-in mice exhibited aggravated inflammation and increased CAC tumorigenesis. In vitro, SHP2E76K and SHP2WT promoted malignant biological behaviors of CRC cells and induced epithelial-mesenchymal transition (EMT) via the Wnt/β-catenin signaling pathway. Together, our results showed that SHP2E76K acts as an oncogene that promotes the tumorigenesis and metastasis of CRC.

Vasodilator-Stimulated Phosphoprotein Biomarkers Are Associated with Invasion and Metastasis in Colorectal Cancer.

Background and Aims:The benefit of adjuvant chemotherapy for stage II colorectal cancer (CRC) patients remains unclear, emphasizing the need for improved prognostic biomarkers to identify patients at risk of metastatic recurrence. To address this unmet clinical need, we examined the expression and phosphorylation status of the vasodilator-stimulated phosphoprotein (VASP) in CRC tumor progression. VASP, a processive actin polymerase, promotes the formation of invasive membrane structures leading to extracellular matrix remodeling and tumor invasion. Phosphorylation of VASP serine (Ser) residues 157 and 239 regulate VASP function, directing subcellular localization and inhibiting actin polymerization, respectively.Methods:The expression levels of VASP protein, pSer157-VASP, and pSer239-VASP were determined by immunohistochemistry in tumors and matched normal adjacent tissue from 141 CRC patients, divided into 2 cohorts, and the association of VASP biomarker expression with clinicopathologic features and disease recurrence was examined.Results:We report that changes in VASP expression and phosphorylation were significantly associated with tumor invasion and disease recurrence. Furthermore, we disclose a novel 2-tiered methodology to maximize VASP positive and negative predictive value performance for prognostication.Conclusion:VASP biomarkers may serve as prognostic biomarkers in CRC and should be evaluated in a larger clinical study.

Correction: Expression of MYSM1 is associated with tumor progression in colorectal cancer.

[This corrects the article DOI: 10.1371/journal.pone.0177235.].

MicroRNA‑337 inhibits colorectal cancer progression by directly targeting KRAS and suppressing the AKT and ERK pathways.

Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death worldwide. Tumour progression and development in CRC is a multi-step process involving a large number of genetic and epigenetic alterations. Previous studies indicated that abnormally expressed microRNAs play critical roles in CRC through regulation of oncogenic and tumour-suppressor genes. Hence, determination of the function of microRNAs may provide novel therapeutic targets for CRC diagnosis and treatments. MicroRNA‑337 (miR‑337) has been reported to be downregulated in several cancer types. However, the expression, function and underlying mechanisms of miR‑337 in CRC have not been clearly elucidated. In this study, miR‑337 was significantly decreased in CRC tissues and cell lines. Low miR‑337 expression level was correlated with lymph node metastasis, distant metastasis and TNM stage of CRC patients. In addition, upregulation of miR‑337 suppressed cell proliferation and invasion and promoted apoptosis in CRC. Based on bioinformatics analysis, we assumed that Kirsten rat sarcoma viral oncogene homolog (KRAS) was directly modulated by miR‑337 in CRC. Luciferase reporter assay demonstrated the direct interaction between miR‑337 and 3'‑UTR of KRAS mRNA. Furthermore, reverse transcription-quantitative polymerase chain reaction and western blot analysis indicated that miR‑337 could negatively regulate endogenous KRAS expression in CRC cells at both mRNA and protein levels. Moreover, KRAS was highly expressed in CRC tissues and inversely correlated with miR‑337 expression in CRC tissues. KRAS knockdown recapitulates effects similar to those induced by miR‑337 overexpression in CRC cells, whereas KRAS overexpression partially restored the tumour suppressive effects of miR‑337. Besides, ectopic expression of miR‑337 inactivates the AKT and ERK signalling pathways in CRC. These results suggested that miR‑337 may act as a tumour suppressor during the process of CRC malignant transformation by interacting with KRAS.

Role of HSPA1L as a cellular prion protein stabilizer in tumor progression via HIF-1α/GP78 axis.

The cellular prion protein (PrPC) is associated with metastasis, tumor progression and recurrence; however, the precise mechanisms underlying its action is not well understood. Our study found that PrPC degradation decreased tumor progression in colorectal cancer (CRC). In a CRC cell line and human CRC tissue exposed to hypoxia, induced heat-shock 70-kDa protein-1-like (HSPA1L) expression stabilized hypoxia-inducible factor-1α (HIF-1α) protein and promoted PrPC accumulation and tumorigenicity in vivo. PrPC was degraded via the proteasome pathway mediated by the ubiquitin-protein E3 ligase glycoprotein 78 (GP78), which interacts directly with PrPC. However, hypoxia-induced HSPA1L interacted with GP78 and inhibited its functions. HSPA1L knockdown facilitated the interaction of GP78 and PrPC, thereby increasing PrPC ubiquitination. Thus, GP78 was identified as the ubiquitinase for PrPC, thereby revealing an essential mechanism that controls PrPC levels in CRC. Our results suggest that the HSPA1L/HIF-1α/GP78 axis has a crucial role in PrPC accumulation during tumor progression.

Estrogen Receptor β as a Prognostic Marker of Tumor Progression in Colorectal Cancer with Familial Adenomatous Polyposis and Sporadic Polyps

The incidence of colorectal cancer (CRC) is lower in women than in men, and sex steroids can be considered contributing factors because oral contraception usage and estrogen replacement therapy are associated with decreased risk. Conversely, colorectal polyp development in familial adenomatous polyposis (FAP) begins during puberty. The objectives were to evaluate the relationship between the expression of these hormone receptors and adenoma-carcinoma progression, CRC stage and overall survival. We studied 120 A.C. Camargo Cancer Center patients diagnosed with either FAP-associated or spontaneous adenomatous polyps or CRC to determine the immunohistochemical expression levels of estrogen receptor (ER)-α, ER-β and the progesterone and androgen receptors (480 analyses). The ER-β expression levels differed between the groups: the group with FAP polyps had lower ER-β expression than that of the sporadic polyp group. With transformation of the sporadic polyps to cancer, there was a considerable decrease in ER-β expression (from 90% with strong expression to 80% with absent or weak expression) (p<0.001). The ER-β expression was lower in T3/T4 tumors than in T1/T2 tumors (p=0.015). The 5-year overall survival of CRC patients positively expressing ER-β exceeded that of patients without detectable expression levels (74.8% vs. 44.3%, respectively; p=0.035). There was no significant expression of the androgen or progesterone receptor or ER-α among the groups. Differences in ER-β expression represent a potential mechanism through which estrogen might alter the susceptibility to colon cancer, thereby confirming the possibility of a protective role of estrogen against colorectal carcinogenesis.

Abstract 5805: Myosin 1e colocalization with β1-intergin and association with tumor progression in colorectal cancer

Abstract For colorectal cancer (CRC), the risk of relapse among stage II and stage III a/b patients is 20-30% and the benefit of treating these patients with chemotherapy is uncertain. As a result, many patients are undertreated, putting them at increased risk for disease relapse, or overtreated, exposing them to unnecessary and harmful chemotherapy with little potential benefit. Therefore, defining prognostic biomarkers to more accurately determine each person’s risk of relapse and need for chemotherapy is a priority in CRC research. Promising targets for biomarker discovery are actin-binding proteins. As a broad class, these proteins regulate the actin cytoskeleton and serve as direct, proximal regulators of invasive and metastatic phenotypes. Further, the prognostic utility of several of these proteins has recently been reported in the literature. Myosin 1e (Myo1e) a long-tailed, class I myosin, is one such protein with proposed clinical utility as a prognostic biomarker. In kidney podocyte cells, Myo1e regulates endocytosis, adhesion, migration, and invadosome dynamics. Despite its expression in numerous cancers, the functional role of Myo1e specifically in cancer cells and its association with tumor progression remains elusive. To define a role in cancer cells, the localization of Myo1e was examined in vitro by immunofluorescence in T84 human CRC cells. Myo1e co-localized with actin, cortactin and β1 integrin at membrane ruffles, which regulate integrin endocytosis and trafficking. Interestingly, both Myo1e and β1 integrin also co-localized with caveolin-1, a regulator of integrin endocytosis, suggesting Myo1e expression may regulate caveolae-dependent integrin endocytosis and trafficking. To evaluate potential prognostic utility, Myo1e expression in colorectal tumors and matched normal adjacent tissue (NAT) was examined by immunohistochemistry in a tissue microarray constructed from duplicate tissue cores from 119 CRC patients. The patient cohort was well balanced across TNM stage: stage 0 (10.1%), stage 1 (20.2%), stage 2 (26.9%), stage 3 (31.1%), and stage 4 (12.6%), and the majority (68.9%) of CRC tissues examined were of moderate tumor grade. The ratio of Myo1e expression in tumors compared to NAT was significantly correlated with clinicopathologic indicators of disease progression, including clinical stage, depth of invasion at the primary tumor (T-score), and lymph node metastasis. Together, these data suggest Myo1e expression correlates with tumor progression and may regulate invasive phenotypes through integrin trafficking pathways. Examining the prognostic utility and biologic function of Myo1e may a define a novel biomarker with translational utility for improved clinical management of colorectal cancer patients. Citation Format: Jeffrey Pfannenstein, Filippo Bori, Alessandro Bombonati, David Zuzga. Myosin 1e colocalization with β1-intergin and association with tumor progression in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5805. doi:10.1158/1538-7445.AM2017-5805

Expression of MYSM1 is associated with tumor progression in colorectal cancer.

Colorectal cancer, the third most common cancer in both men and women, has gradually increased in recent years. MYSM1has been investigated as a regulator of hematopoiesis and lymphocyte development in human. It has been reported that some tumor-related genes were modulated by MYSM1. However, its exact role in cancer development remains unclear. Herein, we aimed to examine the expression level of MYSM1 in tumor tissues and its correlation with clinicopathology and survivals of patients with colorectal cancer (CRC).MYSM1expressions in tumor specimens resected from 123 CRC patients were detected by immunochemistry and Western blot analysis. The results showed that MYSM1 was significantly highly expressed in carcinoma tissues compared with adjacent normal mucosa tissues (P<0.05). Correlation analyses by Pearson’s chi-square test demonstrated that MYSM1 in tumors was positively correlated with tumor status (pathological assessment of the primary tumor (pT, P<0.001), regional lymph nodes (pN, P = 0.013), distant metastasis (pM, P<0.001)) and clinic stage (P<0.001); Whereas, MYSM1 was not associated with tumor size of CRC patients and was positively associated with tumor differentiation grade (P = 0.015). Patients with positiveMYSM1expression showed poor survival compared with the MYSM1 negative group (P<0.001).Simultaneously, multivariate Cox regression analysis indicated thatMYSM1 expression in tumor cells was an independent factor for reduced overall survival in CRC patients (P<0.001).Additionally,MYSM1 in CRC SW480 cells was silenced by small interference RNA (siRNA) technology. Scratch assay and Transwell assay showed that MYSM1 silencing decreased migration and invasion abilities of SW480 cells. These data suggested that expression of MYSM1 was associated with the progression of CRC and might be a potential biomarker for clinical prognosis.

AF1q Mediates Tumor Progression in Colorectal Cancer by Regulating AKT Signaling.

The up-regulation of ALL1-fused gene from chromosome 1q (AF1q) is commonly seen in aggressive hematologic malignancies as well as in several solid tumor tissues. However, its expression and intrinsic function in human colorectal cancer (CRC) remains largely undefined. To explore the role of AF1q in human CRC progression, AF1q expression was analyzed in human CRC tissue samples and CRC cell lines. Clinical specimens revealed that AF1q was up-regulated in human CRC tissues, and that this up-regulation was associated with tumor metastasis and late tumor, lymph node, metastasis (TNM) stage. AF1q knockdown by shRNA inhibited tumor cell proliferation, migration, invasion, and epithelial-mesenchymal transition in vitro, as well as tumorigenesis and liver metastasis in vivo, whereas these effects were reversed following AF1q overexpression. These AF1q-mediated effects were modulated by the protein kinase B (AKT) signaling pathway, and inhibition of AKT signaling attenuated AF1q-induced tumor promotion. Thus, AF1q contributes to CRC tumorigenesis and progression through the activation of the AKT signaling pathway. AF1q might therefore serve as a promising new target in the treatment of CRC.

RGC32 induces epithelial-mesenchymal transition by activating the Smad/Sip1 signaling pathway in CRC

Response gene to complement 32 (RGC32) is a transcription factor that regulates the expression of multiple genes involved in cell growth, viability and tissue-specific differentiation. However, the role of RGC32 in tumorigenesis and tumor progression in colorectal cancer (CRC) has not been fully elucidated. Here, we showed that the expression of RGC32 was significantly up-regulated in human CRC tissues versus adjacent normal tissues. RGC32 expression was significantly correlated with invasive and aggressive characteristics of tumor cells, as well as poor survival of CRC patients. We also demonstrated that RGC32 overexpression promoted proliferation, migration and tumorigenic growth of human CRC cells in vitro and in vivo. Functionally, RGC32 facilitated epithelial-mesenchymal transition (EMT) in CRC via the Smad/Sip1 signaling pathway, as shown by decreasing E-cadherin expression and increasing vimentin expression. In conclusion, our findings suggested that overexpression of RGC32 facilitates EMT of CRC cells by activating Smad/Sip1 signaling.