Invasion Of Colorectal Cancer Cells Research Articles

Auranofin inhibits the occurrence of colorectal cancer by promoting mTOR-dependent autophagy and inhibiting epithelial-mesenchymal transformation.

Colorectal cancer (CRC) is one of the world's most common and deadly cancers. According to GLOBOCAN2020's global incidence rate and mortality estimates, CRC is the third main cause of cancer and the second leading cause of cancer-related deaths worldwide. The US Food and Drug Administration has approved auranofin for the treatment of rheumatoid arthritis. It is a gold-containing chemical that inhibits thioredoxin reductase. Auranofin has a number of biological activities, including anticancer activity, although it has not been researched extensively in CRC, and the mechanism of action on CRC cells is still unknown. The goal of this research was to see how Auranofin affected CRC cells in vivo and in vitro . The two chemical libraries were tested for drugs that make CRC cells more responsive. The CCK-8 technique was used to determine the cell survival rate. The invasion, migration, and proliferation of cells were assessed using a transwell test and a colony cloning experiment. An electron microscope was used to observe autophagosome formation. Western blotting was also used to determine the degree of expression of related proteins in cells. Auranofin's tumor-suppressing properties were further tested in a xenograft tumor model of human SW620 CRC cells. Auranofin dramatically reduced the occurrence of CRC by decreasing the proliferation, migration, and invasion of CRC cells, according to our findings. Through a mTOR-dependent mechanism, auranofin inhibits the epithelial-mesenchymal transition (EMT) and induces autophagy in CRC cells. Finally, in-vivo tests revealed that auranofin suppressed tumor growth in xenograft mice while causing no harm. In summary, auranofin suppresses CRC cell growth, invasion, and migration. Auranofin inhibits the occurrence and progression of CRC by decreasing EMT and inducing autophagy in CRC cells via a mTOR-dependent mechanism. These findings suggest that auranofin could be a potential chemotherapeutic medication for the treatment of human CRC.

MKRN1 promotes colorectal cancer metastasis by activating the TGF-β signalling pathway through SNIP1 protein degradation

BackgroundThe Makorin ring finger protein 1 (MKRN1) gene, also called RNF61, is located on the long arm of chromosome 7 and is a member of the RING finger protein family. The E3 ubiquitin ligase MKRN1 is closely linked to tumour development, but the exact mechanism needs to be elucidated. In this study, we aimed to investigate the specific mechanism and role of MKRN1 in colorectal cancer (CRC) development.MethodsMKRN1 expression in CRC was analysed using the Cancer Cell Line Encyclopaedia and the Cancer Genome Atlas (TCGA) databases. Rectal tumour tissues were frozen to explore the MKRN1 expression in CRC and its clinical significance. The impact of MKRN1 on CRC cell proliferation and migration was observed using CCK8, colony formation, wound healing, and transwell assays. A combination of MKRN1 quantitative proteomics, ubiquitination modification omics analysis, and a string of in vitro and in vivo experiments revealed the potential mechanisms by which MKRN1 regulates CRC metastasis.ResultsMKRN1 expression was significantly elevated in CRC tissues compared to paracancerous tissues and was positively linked with prognosis (P < 0.01). MKRN1 downregulation inhibits CRC cell proliferation, migration, and invasion. Conversely, MKRN1 overexpression promotes the proliferation, migration, and invasion of CRC cells. Mechanistically, MKRN1 induces epithelial-mesenchymal transition (EMT) in CRC cells via ubiquitination and degradation of Smad nuclear-interacting protein 1 (SNIP1). Furthermore, SNIP1 inhibits transforming growth factor-β (TGF-β) signalling, and MKRN1 promotes TGF-β signalling by degrading SNIP1 to induce EMT in CRC cells. Finally, using conditional knockout mice, intestinal lesions and metastatic liver microlesions were greatly reduced in the intestinal knockout MKRN1 group compared to that in the control group.ConclusionsHigh MKRN1 levels promote TGF-β signalling through ubiquitination and degradation of SNIP1, thereby facilitating CRC metastasis, and supporting MKRN1 as a CRC pro-cancer factor. The MKRN1/SNIP1/TGF-β axis may be a potential therapeutic target in CRC.

SNORD11B-mediated 2'-O-methylation of primary let-7a in colorectal carcinogenesis.

Evidence indicates that small nucleolar RNAs (snoRNAs) participate in tumorigenesis and development and could be promising biomarkers for colorectal cancer (CRC). Here, we examine the profile of snoRNAs in CRC and find that expression of SNORD11B is increased in CRC tumor tissues and cell lines, with a significant positive correlation between SNORD11B expression and that of its host gene NOP58. SNORD11B promotes CRC cell proliferation and invasion and inhibits apoptosis. Mechanistically, SNORD11B promotes the processing and maturation of 18 S ribosomal RNA (rRNA) by mediating 2'-O-methylated (Nm) modification on the G509 site of 18 S rRNA. Intriguingly, SNORD11B mediates Nm modification on the G225 site of MIRLET7A1HG (pri-let-7a) with a canonical motif, resulting in degradation of pri-let-7a, inhibition of DGCR8 binding, reduction in mature tumor suppressor gene let-7a-5p expression, and upregulation of downstream oncogene translation. SNORD11B performs comparably to CEA and CA199 in diagnosing CRC. High expression of SNORD11B is significantly correlated with a more advanced TNM stage and lymph node metastasis, which indicates poor prognosis.

The novel angiogenesis regulator circFAM169A promotes the metastasis of colorectal cancer through the angiopoietin-2 signaling axis.

Angiogenesis plays an important role in the metastasis of cancers. However, the mechanisms whereby circular RNAs (circRNAs) regulate angiogenesis and affect cancer metastasis are still unclear. We used gene set variation and Spearman's correlation analyses to identify novel angiogenesis-related circRNAs, including circFAM169A. The Kyoto Encyclopedia of Genes and Genomes and Gene Ontology were used to assess the potential biological function of circFAM169A. A quantitative reverse transcription-PCR (qRT-PCR) analysis of 20 pairs of colorectal cancer (CRC) samples was performed to detect the expression level of circFAM169A. Transwell assays, tube formation assays, and nude mouse metastatic tumor models were used to study the function of circFAM169A in CRC. qRT-PCR, dual-luciferase reporter gene assay, RNA antisense purification assay, and Western blot were performed to analyze the competing endogenous RNA mechanism of circFAM169A in promoting CRC angiogenesis. circFAM169A was highly correlated with the hallmark of angiogenesis in CRC patients. It was up-regulated in liver metastasized CRC patients. circFAM169A overexpression promoted the angiogenesis, migration, and invasion of CRC cells while its down-regulation had the opposite effects. In vivo mouse models further highlighted the pro-metastatic role of circFAM169A in CRC. More importantly, we discovered that circFAM169A enhances the expression of angiopoietin-2 by binding to miR-518a-5p.

Promotion of colorectal cancer progression by immune-related lnc-SOX9–4 via suppression of YBX1 poly-ubiquitination and degradation

BackgroundRecent research has highlighted the versatile functions of long non-coding RNAs (lncRNAs) in the onset and progression of various malignancies. Still, insufficient knowledge is available on how lnc-SOX9–4 functions in colorectal cancer (CRC) progression. MethodsBioinformatics analysis was used to identify a novel lncRNA (lnc-SOX9–4), and the expression pattern of the RNA in CRC was verified using qRT-PCR. Gene ontology (GO) term analysis and Gene set enrichment analysis (GSEA) were implemented for the identification of the related mechanisms and roles of lnc-SOX9–4. Immune infiltration analysis was conducted for assessment of how lnc-SOX9–4 is linked to tumor immune cell infiltration level. Both in vitro and in vivo phenotype analyses were conducted for scrutinizing how lnc-SOX9–4 impacts the proliferation and metastasis of CRC. RNA pulldown, mass spectrometry analysis, fluorescent in situ hybridization (FISH), western blotting, and RIP assay aided in verifying lnc-SOX9–4 mechanisms linked to CRC progression. ResultsAn upregulation of lnc-SOX9–4 was observed in the sample CRC cells and tissues. Elevated lnc-SOX9–4 levels showed a positive association with poor clinical prognosis. Lnc-SOX9–4 was closely correlated to several types of immune infiltrating cells. Functionally, the knockdown of lnc-SOX9–4 significantly inhibited CRC cell proliferation, migration, and invasion abilities. Mechanistically, YBX1 was identified as lnc-SOX9–4, specifically interacting protein in the nucleus. Lnc-SOX9–4 could stabilize YBX1 protein levels by inhibiting poly-ubiquitination and degradation of YBX1. Furthermore, phenotype rescue experiments reveal that lnc-SOX9–4 enhanced the CRC cellular potential to proliferate and metastasize by regulating YBX1 levels. ConclusionsLnc-SOX9–4 promoted CRC progression by suppressing cytoplasmic translocation and promoting protein levels of YBX1 can serve as novel treatment targets for diagnosing and treating CRC.

Fusobacterium nucleatum promotes colorectal cancer metastasis by excretion of miR-122-5p from cells via exosomes

Fusobacterium nucleatum (Fn) infection and microRNAs (miRNAs) are closely associated with colorectal cancer (CRC) development, but the mechanism by which Fn regulates tumor-suppressive miRNAs via exosomes and facilitates CRC metastasis remains unclear. Here, we identified that Fn infection significantly increased exosomal miR-122-5p levels in the serum of CRC patients and CRC cell culture supernatants through two miRNA panels of high-throughput sequencing and RT-qPCR analysis. In Fn-infected patients, the serum exosomal levels of miR-122-5p were negatively associated with their expression levels of tissues. Downregulated miR-122-5p was demonstrated to enhance the migration, invasion, and metastasis abilities of CRC cells invivo and invitro. Secretion of miR-122-5p into exosomes is mediated by hnRNPA2B1. Mechanistically, Fn activated the TGF-β1/Smads signaling pathway to promote EMT by regulation of the miR-122-5p/FUT8 axis. In conclusion, Fn infection may stimulate CRC cells to excrete exosome-wrapped miR-122-5p, and activate the FUT8/TGF-β1/Smads axis to promote metastasis.

Circular RNA circSP5 promotes liver metastasis of colorectal cancer via SP5-mediated BAMBI transcription.

Liver metastasis of colorectal cancer (CRC) is a major cause of cancer morbidity and mortality. Circular RNAs (circRNAs) have been widely reported to be implicated in cancer metastasis. This study aims to investigate the effect of circSP5 (has_circ_0057010) on liver metastasis of CRC. Quantitative real-time PCR (RT-qPCR) analysis was performed to detect gene expression. The level of proteins was measured by western blot. The migration and invasion of CRC cells were assessed by wound healing assay and transwell assay. In vivo assays were performed after the construction of the CRC xenograft model and CRC model with liver metastasis. Mechanism analyses were performed via RNA-binding protein immunoprecipitation (RIP), RNA pulldown, luciferase reporter, chromatin immunoprecipitation (ChIP), and DNA pulldown assays. We found that circSP5 is significantly overexpressed in CRC with liver metastasis and its depletion suppresses the progression of CRC with liver metastasis in vitro and in vivo. Moreover, circSP5 enhances the expression of Sp5 transcription factor (SP5) via competitively sponging microRNA (miR)-1249-3p and could regulate BMP and activin membrane-bound inhibitor (BAMBI) via transcriptional activation. CircSP5 promotes the migration, invasion, and epithelial-mesenchymal transition (EMT) of CRC cells via BAMBI. In sum, circSP5 promotes liver metastasis of CRC by up-regulating SP5-mediated BAMBI transcription.

ELAPOR1 suppresses tumor progression in colorectal cancer and indicates favorable prognosis.

The role of ELAPOR1 has been evaluated in several cancers but has not been elucidated in colorectal cancer (CRC). To investigate the role of ELAPOR1 in CRC. In the present study, the correlation between ELAPOR1 and survival of CRC patients in TCGA-COAD-READ datasets was predicted, and the difference in ELAPOR1 expression between tumor and normal tissues was analyzed. ELAPOR1 expression in CRC tissues was measured by immunohistochemistry. Then, ELAPOR1 and ELAPOR1-shRNA plasmids were constructed and transfected into SW620 and RKO cells. The effects were assessed by CCK-8, colony formation, transwell, and wound healing assays. Transcriptome sequencing and bioinformatics analysis were performed on the genes before and after ELAPOR1 overexpression in SW620 cells; the differentially expressed genes were substantiated by real-time quantitative reverse transcription PCR. High level of ELAPOR1 is associated with favorable disease-free survival and overall survival. Compared to normal mucosa, ELAPOR1 is lower in CRC. Moreover, ELAPOR1 overexpression significantly inhibits cell proliferation and invasion in vitro in SW260 and RKO cells. Conversely, ELAPOR1-shRNA promotes CRC cell proliferation and invasion. Among the 355 differentially expressed mRNAs identified, 234 were upregulated and 121 were downregulated. Bioinformatics indicated that these genes are involved in receptor binding, plasma membrane, negative regulation of cell proliferation, as well as common cancer signaling pathways. ELAPOR1 plays an inhibitory role in CRC and may be used as a prognostic indicator and a potential target for treatment.

Long noncoding RNA BBOX1-AS1 increased radiotherapy sensitivity in colorectal cancer by stabilizing and activating PFK1

PurposeOur study explored the effect of long noncoding RNA BBOX1-AS1 on colorectal cancer (CRC) radiosensitivity in vivo and in vitro. MethodsDifferentially expressed lncRNAs in CRC were screened using a bioinformatics database and an online prediction website. The expression of BBOX1-AS1 in tissue samples was analyzed via real-time quantitative PCR (RT-qPCR). Subcellular localization of BBOX1-AS1 in CRC cells was analyzed using fluorescence in situ hybridization (FISH). The correlation between BBOX1-AS1 and PFK1 expression levels in CRC tissues was analyzed via Pearson's correlation coefficient. The effect of BBOX1-AS1 on PFK1 stability was investigated using RNA and protein stability testing. RNA Binding Protein Immunoprecipitation (RIP) and RNA pull-down assays were used to confirm the binding of BBOX1-AS1 to PFK1. ResultsBBOX1-AS1 was highly expressed in CRC and associated with poor prognosis. Similarly, it was highly expressed in CRC tissues and CRC cell lines. In addition, BBOX1-AS1 promoted the proliferation, invasion, migration, and glycolysis of CRC cells and inhibited apoptosis. RIP and RNA pull-down experiments confirmed that BBOX1-AS1 bound to PFK1. RNA stability and protein stability experiments showed that BBOX1-AS1 affected the stability of PFK1 mRNA and protein. Furthermore, we confirmed that BBOX1-AS1 increased radiation resistance through the regulation of PFK1 expression. ConclusionsBBOX1-AS1 promoted the proliferation, invasion, migration, and glycolysis of CRC cells through stabilization of the expression of PFK1. BBOX1-AS1 also inhibited CRC cell apoptosis and increased radiotherapy resistance in CRC cells.

Paeoniflorin inhibits colorectal cancer cell stemness through the miR-3194-5p/catenin beta-interacting protein 1 axis.

Paeoniflorin (PF) is a natural plant ingredient with remarkable antitumor effects. Herein, we investigated the biological effects and mechanism of PF in colorectal cancer (CRC) cell stemness. The messenger RNA (mRNA) and protein expressions were assessed using quantitative real-time polymerase chain reaction and western blot. The viability, proliferation, and migration and invasion of CRC cells were evaluated using cell counting kit-8, clone-formation, and transwell migration and invasion assays, respectively. The sphere-formation capacity was determined using the sphere-formation assay. A dual-luciferase reporter gene assay was employed to analyze the interaction between miR-3194-5p and catenin beta-interacting protein 1 (CTNNBIP1). The viability, migration, invasion, epithelial-mesenchymal transition, and stemness of CRC cells were repressed by PF. MiR-3194-5p was upregulated in CRC tissues and cells. MiR-3194-5p knockdown suppressed CRC cell stemness, while miR-3194-5p overexpression had the opposite effect. In addition, the inhibition of CRC cell stemness caused by PF was eliminated by miR-3194-5p overexpression. CTNNBIP1 functioned as the target of miR-3194-5p, whose knockdown abrogated the repression of CRC cell stemness and Wnt/β-catenin signaling activation by PF.PF regulated the miR-3194-5p/CTNNBIP1/Wnt/β-catenin axis to repress CRC cell stemness.

Histone Modification of Colorectal Cancer by Natural Products.

Natural products play important roles in the pathogenesis of many human malignancies, including colorectal cancer, and can act as a gene regulator in many cancers. They regulate malignant cell growth through many cellular signal pathways, including Rac family small GTPase 1 (RAC1)/PI3K/AKT (α-serine/threonine-protein kinase), mitogen-activated protein kinase (MAPK), Wnt/β-catenin pathway, transforming growth factor-β (TGF-β), Janus kinase and signal transducer and activator of transcription (JAK-STAT), nuclear factor kappa-B (NF-κB), the Notch pathway, Hippo pathway, and Hedgehog pathway. In this review, we describe the epigenetic roles of several natural products, e.g., platycodin D (PD), ginsenoside Rd, tretinoin, Rutin, curcumin, clove extract, betulinic acid, resveratrol, and curcumin, in colorectal cancer, including their impact on colorectal cancer cell proliferation, apoptosis, invasion, migration, and anti-chemotherapeutic resistance. The aim is to illustrate the epigenetic mechanisms of action of natural products in cancer prevention and treatment, and to provide (1) a theoretical basis for the study of the role of epigenetics in influencing colorectal cancer; (2) new directions for studying the occurrence, development, and prognosis of colorectal cancer; and (3) new targets for treating and preventing colorectal cancer.

Erianin inhibits the growth and metastasis through autophagy-dependent ferroptosis in KRASG13D colorectal cancer.

Colorectal cancer (CRC) is the third most common cause of cancer mortality worldwide. Approximately 40% of CRC patients are KRAS sequence variation, including KRAS G13D mutation (KRASG13D) CRC patients, accounting for approximately 8% of all KRAS mutations in CRC patients and showing little benefit from anti-EGFR therapy. Therefore, there is an urgent need for new and effective anticancer agents in patients with KRASG13D CRC. Here, we identified a natural product, erianin, that directly interacted with purified recombinant human KRASG13D with a Kd of 1.1163 μM, which also significantly improve the thermal stability of KRASG13D. The cell viability assay showed that KRASG13D cells were more sensitive to erianin than KRASWT or KRASG12V cells. In vitro, results showed that erianin suppressed the migration, invasion and epithelial-mesenchymal transition (EMT) of KRASG13D CRC cells. Furthermore, erianin induced ferroptosis, as evidenced by the accumulation of Fe2+ and reactive oxygen species (ROS), lipid peroxidation, and changes in the mitochondrial morphology of KRASG13D CRC cells. Interestingly, we also found that erianin-induced ferroptosis was accompanied by autophagy. Moreover, the occurrence of erianin-induced ferroptosis is reversed by autophagy inhibitors (NH4Cl and Bafilomycin A1) and ATG5 knockdown, suggesting that erianin-induced ferroptosis is autophagy-dependent. In addition, we evaluated the inhibition of tumor growth and metastasis by erianin in vivo using a subcutaneous tumor model and a spleen-liver metastasis model, respectively. Collectively, these data provide novel insights into the anticancer activity of erianin, which is valuable for the further discussion and investigation of the use of erianin in clinical anticancer chemotherapy for KRASG13D CRC.

Vitamin D Inhibits Colorectal Cancer Cell Proliferation, Migration and Invasion via Downregulating the Notch1 Pathway.

Due to its high incidence and mortality rates, colorectal cancer (CRC) has become the focus of research. Vitamin D has anticancer functions in a variety of cancers, but the relationship between vitamin D status and CRC risk and survival is inconclusive. The purpose of this study was to explore the effect of vitamin D on the proliferation and invasion of CRC cells to find an effective way to treat CRC. The results showed that vitamin D could inhibit SW480 cell progression in vitro. The results showed that vitamin D significantly blocked the Notch1 pathways by decreasing NOTCH1 protein expression. In addition, we found that Notch1 overexpression could significantly reverse the inhibitory effect of vitamin D on SW480 cells. These results reveal novel insights into the mechanisms of vitamin D anticancer activity in CRC development and progression.

A novel RIP1-mediated canonical WNT signaling pathway that promotes colorectal cancer metastasis via β -catenin stabilization-induced EMT.

RIP1 (receptor-interacting protein kinase 1) is an important component of TNF-α signaling that contributes to various pathological effects. Here, we revealed new potential roles of RIP1 in controlling WNT/β-catenin canonical signaling to enhance metastasis of colorectal cancer (CRC). First, we showed that WNT3A treatment sequentially increased the expression of RIP1 and β-catenin. Immunohistochemical analyses of human CRC tissue arrays consisting of normal, primary, and metastatic cancers indicated that elevated RIP1 expression might be related to β-catenin expression, carcinogenesis, and metastasis. Intravenous injection of RIP1 over-expressed CRC cells into mice has demonstrated that RIP1 may promote metastasis. Immunoprecipitation (IP) results indicated that WNT3A treatment induces direct binding between RIP1 and β-catenin, and that this stabilizes the β-catenin protein in a manner that depends on the regulation of RIP1 ubiquitination via downregulation of the E3 ligase, cIAP1/2. Elimination of cIAP1/2 expression and inhibition of its ubiquitinase activity enhance WNT3A-induced RIP1 and β-catenin protein expression and binding, which stimulates endothelial-mesenchymal transition (EMT) induction to enhance the migration and invasion of CRC cells in vitro. The results of the in vitro binding assay and IP of exogenous RIP1-containing CRC cells additionally verified the direct binding of RIP1 and β-catenin. RIP1 expression can destroy the β-catenin-β-TrCP complex. Taken together, these results suggest a novel EMT-enhancing role of RIP1 in the WNT pathway and suggest a new canonical WNT3A-RIP1-β-catenin pathway that contributes to CRC malignancy by promoting EMT.

NADPH oxidase 1: A target in the capacity of dimeric ECG and EGCG procyanidins to inhibit colorectal cancer cell invasion

Colorectal cancer (CRC) is prevalent worldwide. Dietary consumption of procyanidins has been linked to a reduced risk of developing CRC. The epidermal growth factor (EGF) receptor (EGFR) signaling pathway is frequently dysregulated in CRC. Our earlier research showed that the procyanidin dimers of epicatechin gallate (ECG) and epigallocatechin gallate (EGCG), through their interaction with lipid rafts, inhibit the EGFR signaling pathway and decrease CRC cell growth. The process of cancer cell invasion and metastasis involves matrix metalloproteinases (MMPs), which are partially EGFR-regulated. This study investigated whether ECG and EGCG dimers can inhibit EGF-induced CRC cell invasion by suppressing the redox-regulated activation of the EGFR/MMPs pathway. Both dimers mitigated EGF-induced cell invasion and the associated increase of MMP-2/9 expression and activity in different CRC cell lines. In Caco-2 cells, both dimers inhibited the activation of the EGFR and downstream of NF-κB, ERK1/2 and Akt, which was associated with decreased MMP-2/9 transcription. EGF induced a rapid NOX1-dependent oxidant increase, which was diminished by both ECG and EGCG dimers and NOX inhibitors (apocynin, Vas-2870, DPI). Both dimers inhibited NOX1 gene expression, as well as NOX1 activity with evidence of direct binding to NOX1. Both dimers, all NOX chemical inhibitors and NOX1 silencing inhibited EGF-mediated activation of the EGFR signaling pathway and the increased MMP-2/9 mRNA levels and activity. Pointing to the relevance of NOX1 on ECG and EGCG dimer effects on CRC invasiveness, silencing of NOX1 also inhibited EGF-stimulated Caco-2 cell invasion. In summary, ECG and EGCG dimers can act inhibiting CRC cell invasion/metastasis both, by downregulating MMP-2 and MMP-9 expression via a NOX1/EGFR-dependent mechanism, and through a direct inhibitory effect on MMPs enzyme activity.

Cadmium promotes colorectal cancer metastasis through EGFR/Akt/mTOR signaling cascade and dynamics

Cadmium (Cd) is a hazardous environmental heavy metal with a prolonged biological half-life. Due to the main route of foodborne exposure, the intestinal tract is particularly vulnerable to Cd-induced toxicity. However, the chronic toxicity and underlying mechanisms of Cd in intestinal diseases, including colorectal cancer (CRC), still remain vague. Herein, we aim to investigate the long-term effects of Cd exposure on CRC development and the key signaling event. Our findings indicate that chronic and low-dose exposure to Cd promoted the invasion and metastasis capability of CRC cells in vitro and in mice, with a marginal increase in cell growth. The expression of cell junction-related genes was down-regulated while those molecules that facilitate cell mobility were significantly increased by Cd exposure. Epidermal growth factor receptor (EGFR) signaling was identified to play the dominant role in Cd-promoted CRC metastasis. Interestingly, Cd activated EGFR in a non-canonical manner that exhibited distinct signaling dynamics from the canonical ligand. In contrast to EGF, which induced transient EGFR signaling and ERK activation, Cd promoted sustained EGFR signaling to trigger Akt/mTOR cascade. The unique signaling dynamics of EGFR induced by Cd provoked responses that preferably enhanced the metastatic capacity rather than the growth. Furthermore, blockade of EGFR abrogated the promoting effects of Cd on the liver metastasis of CRC cells. In conclusion, this study provides a better understanding of the long-term influences of environmental Cd on CRC metastasis and reveals the unique EGFR signaling dynamics induced by Cd exposure.

Cardiac Troponin T (TNNT2) plays a potential oncogenic role in colorectal carcinogenesis

PurposeColorectal cancer (CRC) is the third most common cancer in the world. The purpose of this study was to investigate the role of TNNT2 in the proliferation, migration and invasion of CRC cells and its expression in CRC tissues to better understand the regulatory role of TNNT2 in CRC.MethodsWestern blotting (WB) and qPCR were used to detect the expression of TNNT2 in colorectal cancer tissues and paracancerous tissues. CCK-8, colony formation, Transwell and other experiments were used to clarify the role of TNNT2 in the proliferation, migration and invasion of colorectal cancer cells. Changes in TNNT2, EGFR and HER2 mRNA transcription levels were detected by SYBR Real-Time PCR assay, and the effects of TNNT2 overexpression or knockdown on the expression of EGFR, HER2 and EMT-related proteins in CRC cells were determined by WB. TNNT2 and EGFR intreaction was carried out in HCT116 cells by coimmunoprecipitation experiments.ResultsThe protein and mRNA expression level of TNNT2 in CRC tissues were higher than those in paracancerous tissues. The CCK-8 results suggested that overexpression of TNNT2 significantly promoted the proliferation of HCT116 and RKO cells, and TNNT2 konckdown gets the opposite result; and the colony formation results were the same as tthose of CCK-8 assay. Transwell invasion and migration experiments showed that overexpression of TNNT2 promoted the migration and invasion of HCT116 and PKO cells, and TNNT2 konckdown suppressed the migration and invasion of the these cells. The SYBR Green I real-time PCR method revealed that them RNA levels of TNNT2, EGFR and HER2 in the TNNT2 overexpression group were higher than those in RKO cells. WB showed that overexpressing TNNT2 increased the expression of EGFR and HER2 in HCT16 and RKO cells,decreased the expression of EMT marker E-cadherin, and increased the expression of Vimentin and N-cadherin. Konckdown of TNNT2 decreased the expression of EGFR and HER2, increased the expression of E-cadherin, and decreased the expression of Vimentin and N-cadherin in HCT16 and RKO cells. The immunocoprecipitation experiment showed that there was an interaction between EGFR and TNNT2.ConclusionTNNT2 can promote the proliferation, invasion and metastasis of colorectal cancer cells. There is an interaction between TNNT2 and EGFR protein. TNNT2 can upregulate EGFR and HER2-related proteins in colorectal cancer cells and promote the occurrence of EMT. Therefore, TNNT2 can promote the invasion and metastasis of CRC cells through the EGFR/HER2/EMT signal axis, suggesting that TNNT2 is a potential target of CRC treatment.

Regulatory mechanism of RNA binding motif protein 15-mediated N6 methyladenosine modification in proliferation, invasion, and migration of colorectal cancer cells.

This study aims to explore the regulatory mechanism of RNA binding motif protein 15 (RBM15) on the proliferation, invasion, and migration of colorectal cancer (CRC) cells. RBM15, KLF1, or SIN3A expression in CRC tissues and cells was detected by RT-qPCR or Western blot. CRC cell functions were measured by CCK-8, colony formation, and Transwell assays after RBM15 intervention. MeRIP and RIP measured N6 methyladenosine (m6 A) and IGF2BP3 enrichment on KLF1 mRNA. ChIP and dual-luciferase analyzed KLF1 enrichment on SIN3A promoter. Combined experiments verified the effect of KLF1/SIN3A on CRC cell functions. Lung/liver metastasis models were established to validate the effect of RBM15 on CRC in vivo. RBM15, KLF1, and SIN3A were highly expressed in CRC. RBM15 knockdown reduced the proliferation, invasion, and migration of CRC cells in vitro. Mechanistically, RBM15 facilitated KLF1 mRNA stability and expression through IGF2BP3-dependent m6 A modification, thus promoting KLF1 enrichment on the SIN3A promoter and activating SIN3A transcription. Overexpression of KLF1 or SIN3A reversed the inhibitory effect of RBM15 knockdown on CRC cells. In vivo experiments verified that RBM15 promoted tumorigenesis and lung/liver metastasis via KLF1/SIN3A axis. In conclusion, RBM15 stimulated CRC proliferation and metastasis by promoting the KLF1/SIN3A axis through IGF2BP3-dependent m6 A modification.

Procyanidin C1 inhibits tumor growth and metastasis in colon cancer via modulating miR-501-3p/HIGD1A axis

IntroductionAlthough colon (COAD) and rectal adenocarcinoma (READ) combined to refer to colorectal cancer (CRC), substantial clinical evidence urged that CRC should be treated as two different cancers due to compared with READ, COAD showed higher morbidity and worse 5-year survival. ObjectivesThis study has tried to screen for the crucial gene that caused the worse prognosis and investigate its mechanism for mediating tumor growth and metastases in COAD. Meanwhile, the potential anti-COAD compound implicated in this mechanism was identified and testified from 1,855 food-borne chemical kits. This study aims to bring a new perspective to the development of new anti-COAD drugs and personalized medicine for patients with COAD. Methods and resultsThe survival-related hub genes in COAD and READ were screened out from The Cancer Genome Atlas (TCGA) database and the results showed that HIGD1A, lower expressed in COAD than in READ, was associated with poor prognosis in COAD patients, but not in READ. Over-expressed HIGD1A suppressed CRC cell proliferation, invasion, and migration in vitro and in vivo. Meanwhile, the different expressed microRNA profiles between COAD and READ showed that miR-501-3p was highly expressed in COAD and inhibited HIGD1A expression by targeting 3′UTR of HIGD1A. MiR-501-3p mimics promoted cell proliferation and metastasis in CRC cells. In addition, Procyanidin C1 (PCC1), a kind of natural polyphenol has been verified as a potential miR-501-3p inhibitor. In vitro and in vivo, PCC1 promoted HIGD1A expression by suppressing miR-501-3p and resulted in inhibited tumor growth and metastasis. ConclusionThe present study verified that miR-501-3p/HIGD1A axis mediated tumor growth and metastasis in COAD. PCC1, a flavonoid that riched in food exerts anti-COAD effects by inhibiting miR-501-3p and results in the latter losing the ability to suppress HIGD1A expression. Subsequently, unfettered HIGD1A inhibited tumor growth and metastasis in COAD.

Retracted] MicroRNA‑383 suppresses cell proliferation and invasion in colorectal cancer by directly targeting paired box6.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the cell migration and invasion assay data shown in Figs.2C and 5C were strikingly similar to data appearing in different form in other articles by different authors at different research institutes, several of which have been retracted. Owing to the fact that the contentious data in the above article were already under consideration for publication, or had already been published, prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 17: 6893‑6901, 2018; DOI: 10.3892/mmr.2018.8682].