Colon Cancer Growth Research Articles

Epigenetically suppressed tumor cell intrinsic STING promotes tumor immune escape

DNA sensing through the cGAS-STING pathway plays an important role in cancer immunosurveillance. Pharmaceutical activation of STING in the tumor environment is considered an attractive approach to induce anti-tumor immunity, but had limited efficacy in the clinic. Several studies have found that STING is epigenetically silenced in many tumors, including colon cancer. This suggests that STING silencing in tumor cells contributes to immune escape and may limit the application of STING agonists. We previously found that inhibition of the KDM5 family histone demethylases restored STING expression in human breast cancer cells and activated the cGAS-STING pathway. In this study, we used MC38 and CT26 syngeneic mouse colorectal cancer models to show that loss of STING in tumor cells accelerates tumor growth. KDM5 inhibitors activate STING expression in mouse colorectal cancer cells and suppress colon cancer growth in immune competent mice in a STING-dependent manner. This study highlights KDM5 inhibitors as novel immune modulators in cancer therapies.

Oncogenic RAS Networks Suppression: Reversibly Ionic Oligonucleotide‐Based Nanoparticles Caged microRNA‐143 Inhibit KRAS‐Mutated Colon Cancer Growth in Tumor‐Bearing Mice

AbstractOncogenic RAS has been a particular focus of attention as a pharmacological target over the last four decades. Tumor‐suppressor microRNA‐143 (miR‐143) silences oncogenic KRAS networks, but it requires a nucleic acid delivery vehicle for clinical application. DNA‐ or RNA‐based nucleic acid structures (NASs) are attractive as vehicles that can form unique sequence‐based structures. However, for the biological application of NASs, it is still challenging to create a nanostructure that is stable under physiological conditions by reducing intramolecular repulsion due to negative charges. Here, a novel NAS (named RIONmiR‐143: reversibly ionic oligonucleotide‐based nanoparticles caged miR‐143) is created by self‐assembly involving hybridization and electrostatic interaction via chemically modified oppositely charged ion oligonucleotides. RIONmiR‐143 are nanoparticles of about 70 nm in diameter with improved nuclease resistance under physiological conditions. Moreover, RIONmiR‐143 inhibit the expression of proteins in KRAS networks and cell growth in a dose‐dependent manner in KRAS‐mutated DLD‐1 cells. The anti‐tumor activity of RIONmiR‐143 is demonstrated in a DLD‐1 cell‐bearing mouse model, with a fourfold decrease in tumor volume compared with NakedmiR‐143. This report presents RIONmiR‐143 as a new option for oncogenic KRAS‐targeting medicine, which can be used as a potent nucleic acid delivery platform.

Th2 cells inhibit growth of colon and pancreas cancers by promoting anti-tumorigenic responses from macrophages and eosinophils

BackgroundImmunotherapy of gastrointestinal cancers is challenging; however, several lines of evidence suggest that adoptive transfer of stimulated or modified immune cells support not only protective role of immune cells in tumor microenvironment, but actively participate in the elimination of cancer cells.MethodsIn vivo studies employing cancer cell-derived allograft murine models of gastrointestinal cancers were performed. The effects of T helper (Th) 2 cells on gastrointestinal cancers growth and tumor microenvironment composition using adoptive transfer of Th2 cells, interleukin (IL)-5 treatment, and immunofluorescence, multiplex and real-time PCR were explored.ResultsHere, we show that Th2 cells play an essential role in the inhibition of colon and pancreas cancers progression. In murine models of gastrointestinal tumors using adoptive transfer of Th2 cells, we identify that Th2 cells are responsible for generation of apoptotic factors and affect macrophage as well as eosinophil recruitment into tumors where they produce cytotoxic factors. Moreover, we found that Th2 cells lead to IL-5 hypersecretion, which links the anti-tumorigenic function of Th2 cells and eosinophils. Importantly, we noted that recombinant IL-5 administration is also related with inhibition of gastrointestinal tumor growth. Finally, using an in vitro approach, we documented that both Th2 cells and eosinophils are directly responsible for gastrointestinal cancer cell killing.ConclusionsThese data demonstrate the significance of Th2 cells, eosinophils and IL-5 in the inhibition of gastrointestinal tumor growth, and pointed toward tumor microenvironment reprogramming as a Th2 cell-mediated anti-tumorigenic mechanism of action.

ZDHHC9 promotes colon tumor growth by inhibiting effector T cells.

Zinc finger DHHC-type palmitoyltransferase 9 (ZDHHC9) has been reported to play an important role in the occurrence and development of several types of cancer. However, its effects on colon cancer growth remain unclear. Using Gene Expression Profiling Interactive Analysis and Tumor Immune Estimation Resource, data obtained from The Cancer Genome Atlas were analyzed, and the results showed that ZDHHC9 was highly expressed in colon cancer and that patients with higher ZDHHC9 expression levels had a worse prognosis. Inhibition of ZDHHC9 expression promoted the proliferation of colon cancer cells in vitro but decreased their growth in vivo. Additionally, inhibition of ZDHHC9 expression in cancer cells enhanced CD8+ T cell-mediated cytotoxicity in vitro and increased CD8+ T infiltration and activation in vivo. Furthermore, ZDHHC9 promoted IFN-γ-induced JAK/STAT1 activation and upregulated programmed death-ligand 1 (PD-L1) expression in colon cancer cells. In conclusion, the present findings showed that ZDHHC9 promoted colon cancer growth by upregulating the expression of PD-L1 and inhibiting the function of CD8+ T cells.

Protective Factors for Colorectal Cancer

Aspirin and other nonsteroidal anti-inflammatory medicines (NSAIDs) have been shown in a large body of research to be protective against the growth of adenomas and colon cancer. the possible benefit of NSAIDs like aspirin in preventing CRC. Other protective factors have also been found, mostly through observational research, but the potency of some of these correlations is not clear. Dietary regimens of a certain kind may lower the risk of CRC.

Sleeve Gastrectomy Increases Colitis-Associated Colon Tumor Growth Independent of Diet

INTRODUCTION: We have previously found that sleeve gastrectomy (SG) causes increased numbers of tumors in a diet-induced obesity mouse model of colitis-associated cancer (CAC). Here we examine the effects of SG on CAC in lean mice fed a regular diet. METHODS: Twelve-week-old lean C57BL/6J mice were maintained on a normal chow diet and randomized to SG or sham operation. Five weeks postoperatively, CAC was established via one-time injection of azoxymethane (AOM) followed by 2-week-long periods of dextran sulfate sodium (DSS) administration. Colitis severity was scored from 0 to 12 by measuring weight loss, stool consistency, and hematochezia. The number of colonic tumors and total tumor surface area were measured at sacrifice 46 days after DSS and compared using Welch’s t-test. RESULTS: CAC tumors were significantly larger in lean SG mice compared with sham (0.67 cm2 vs 0.29 cm2; p = 0.046; Figs. 1A, 1B). However, lean SG mice developed similar levels of colitis as sham (maximum colitis severity 4.7 vs 4.1; data not shown) and similar numbers of tumors (4.4 vs 3.6; p = 0.61; Fig. 1C). In contrast, in obese mice, SG leads to increased tumor numbers (5.5 vs 1.4; p = 0.0003; Fig. 1D) as well as increased colitis severity and larger tumors (data not shown).Figure 1CONCLUSION: SG increases tumor size in a mouse CAC model independent of diet and obesity. SG-induced increases in tumor number and colitis severity are present in diet-induced obese but not lean mice. These data suggest that surgery, diet, and obesity have distinct roles in colon cancer initiation and growth.

CircHADHA-augmented autophagy suppresses tumor growth of colon cancer by regulating autophagy-related gene via miR-361.

Colon cancer undergoes a traditional pathway from colon polyps to colon cancer. It is of great significance to investigate the key molecules involved in carcinogenesis from polyps to malignancies. Circular RNAs (circRNAs) are stably expressed in human body fluids such as plasma. Here, we demonstrated a differential expression pattern of plasma circRNAs in healthy individuals, colon polyp patients and colon cancer patients using circRNA Arraystar microarray. We explored that circRNA HADHA (circHADHA) was upregulated in plasma from polyp patients, whereas it was downregulated in plasma from colon cancer patients. Overexpression of circHADHA promoted autophagy in colon epithelial cells. Moreover, in colon cancer cells, overexpression of circHADHA promoted autophagy, whereas it inhibited cell proliferation and colony formation. CircHADHA increased the expression of ATG13 via miR-361 in both colon epithelial and cancer cells. ATG13 knockdown reduced autophagy even in the presence of circHADHA in colon cancer cells. Furthermore, the growth of circHADHA-overexpressing colon cancer cell-derived xenograft tumors was significantly decreased compared with control tumors in nude mice. In conclusion, circHADHA was differentially expressed in the plasma of healthy individuals, colon polyp patients and colon cancer patients. CircHADHA promoted autophagy by regulating ATG13 via miR-361 in both colon epithelial and cancer cells. CircHADHA suppressed tumor growth by inducing cell autophagy in colon cancer cells. CircHADHA potentially serves as a biomarker for screening of precursor colon cancer and a therapeutic target for colon cancer treatment.

Tenglong Buzhong granules inhibits the growth of SW620 human colon cancer.

To observe the anticancer effects of the granular preparation of Tenglong Buzhong decoction (,TBD), i.e Tenglong Buzhong granules (, TBG), in human SW620 colon cancer. BALB/c nude mice were subcutaneously transplanted with SW620 cells, and treated with TBG (2.56 g/kg, once per day) and/or 5-Fu (104 mg/kg, once per week) for 21 d. Apoptosis, Caspase activities and cellular senescence were measured by commercial kits. The protein expression and phosphorylation were detected by Western blot or immunohistochemistry. TBG and 5-Fu inhibited tumor growth. The tumor inhibition rate of the TBG, 5-Fu, and TBG+5-Fu groups was 42.25%, 51.58%, and 76.08%, respectively. Combination of TBG and 5-Fu showed synergetic anti-cancer effects. TBG and 5-Fu induced apoptosis, activated caspase-3, -8, and -9, increased SMAC expression, inhibited XIAP expression. TBG induced cellular senescence, upregulated cyclin-dependent kinase inhibitor 1a (CDKN1a) and cyclin-dependent kinase inhibitor 2a (CDKN2a) expression, and inhibited phosphorylation of retinoblastoma-associated protein (RB) and expression of cyclin E1 (CCNE1) and cyclin-dependent kinases (CDK) 2. TBG also inhibited angiogenesis accompanied by downregulation of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α). TBG inhibits SW620 colon cancer growth, induces apoptosis SMAC-XIAP-Caspases signaling, induces cellular senescence through CDKN1a/CDKN2a-RB-E2F signaling, inhibits angiogenesis by down-regulation of HIF-1α and VEGF, and enhances the effects of 5-Fu.

Negative regulation of CDKN1A by the histone methyltransferase EHMT2 for cell growth in colorectal cancer

The epigenetic regulation of oncogenes and tumor suppressor genes by histone methyltransferases is an important process for colon cancer growth and metastasis. Although various epigenetic modifiers have been recognized as attractive therapeutic targets for colon cancer treatment, alternative epigenetic regulation in colon cancer for reducing side effects and increasing the effectiveness of treatments has not been thoroughly explored. In this study, we identified CDKN1A as a direct target for EHMT2 by RNA-sequencing and found increased growth suppression via upregulation of CDKN1A by EHMT2 knockdown. In addition, using a 3-dimensional culture system for spheroid formation with an ultralow attachment plate, we confirmed EHMT2-related growth suppression and CDKN1A regulation. Thus, we suggest that EHMT2 may be a therapeutic target for colon cancer treatment, and an EHMT2 inhibitor should be developed for the effective treatment of colon cancer.

Beta-Glucan from S. cerevisiae Protected AOM-Induced Colon Cancer in cGAS-Deficient Mice Partly through Dectin-1-Manipulated Macrophage Cell Energy.

Although the impacts of Saccharomyces cerevisiae on cancers are mentioned, data on its use in mice with cyclic GMP-AMP synthase deficiency (cGAS-/-) are even rarer. Here, 12 weeks of oral administration of S. cerevisiae protected cGAS-/- mice from azoxymethane (AOM)-induced colon cancers, partly through dysbiosis attenuation (fecal microbiome analysis). In parallel, a daily intralesional injection of a whole glucan particle (WGP; the beta-glucan extracted from S. cerevisiae) attenuated the growth of subcutaneous tumor using MC38 (murine colon cancer cell line) in cGAS-/- mice. Interestingly, the incubation of fluorescent-stained MC38 with several subtypes of macrophages, including M1 (using Lipopolysaccharide; LPS), M2 (IL-4), and tumor-associated macrophages (TAM; using MC38 supernatant activation), could not further reduce the tumor burdens (fluorescent intensity) compared with M0 (control culture media). However, WGP enhanced tumoricidal activities (fluorescent intensity), the genes of M1 pro-inflammatory macrophage polarization (IL-1β and iNOS), and Dectin-1 expression and increased cell energy status (extracellular flux analysis) in M0, M2, and TAM. In M1, WGP could not increase tumoricidal activities, Dectin-1, and glycolysis activity, despite the upregulated IL-1β. In conclusion, S. cerevisiae inhibited the growth of colon cancers through dysbiosis attenuation and macrophage energy activation, partly through Dectin-1 stimulation. Our data support the use of S. cerevisiae for colon cancer protection.

A Probody T Cell-Engaging Bispecific Antibody Targeting EGFR and CD3 Inhibits Colon Cancer Growth with Limited Toxicity.

A conditionally active EGFR-CD3 T cell-engaging Probody therapeutic expands the safety window of bispecific antibodies while maintaining efficacy in preclinical solid tumor settings.

Ginger polysaccharide UGP1 suppressed human colon cancer growth via p53, Bax/Bcl-2, caspase-3 pathways and immunomodulation

In previous study, we got a purified ginger polysaccharide UGP1 and verified its significant antitumor activities on colon cancer HCT116 cells. In this article, we aimed to illustrate the underlying mechanism of UGP1 exerted antitumor activities on colon cancer by using in vitro cell models and in vivo animal models. The results demonstrated that UGP1 could induce S-phase cell cycle arrest, up-regulate the expression of Bax and p53, down-regulate the expression of Bcl-2, and activate the downstream protein caspase-9 and caspase-3, which was related to intrinsic apoptosis pathway on HCT116 cells. Moreover, UGP1 significantly stimulated RAW264.7 cell proliferation and secretion activity. Similarly, UGP1 inhibited tumor proliferation on tumor-bearing mice, increased the expression of p53 and the ratio of Bax/Bcl-2, enhanced the secretion of pro-inflammatory cytokines TNF-α, IL-2, IL-6 and decreased the secretion of pro-tumor cytokines TGF-β and bFGF in serum. In conclusion, it indicated that the UGP1 could suppress human colon cancer growth by inducing apoptosis via the regulation of p53, caspase-3, and Bax/Bcl-2 ratio-dependent pathway and regulating immune system activity. This investigation provided basic theoretical mechanism of ginger polysaccharide-exerted antitumor activities, and contributed to develop a possible functional food or adjuvant agent for prevention or treatment of colon cancer.

PH-Binding Motif in PAR4 Oncogene: From Molecular Mechanism to Drug Design.

While the role of G-protein-coupled receptors (GPCR) in cancer is acknowledged, their underlying signaling pathways are understudied. Protease-activated receptors (PAR), a subgroup of GPCRs, form a family of four members (PAR1-4) centrally involved in epithelial malignancies. PAR4 emerges as a potent oncogene, capable of inducing tumor generation. Here, we demonstrate identification of a pleckstrin-homology (PH)-binding motif within PAR4, critical for colon cancer growth. In addition to PH-Akt/PKB association, other PH-containing signal proteins such as Gab1 and Sos1 also associate with PAR4. Point mutations are in the C-tail of PAR4 PH-binding domain; F347 L and D349A, but not E346A, abrogate these associations. Pc(4-4), a lead backbone cyclic peptide, was selected out of a mini-library, directed toward PAR2&4 PH-binding motifs. It effectively attenuates PAR2&4-Akt/PKB associations; PAR4 instigated Matrigel invasion and migration in vitro and tumor development in vivo. EGFR/erbB is among the most prominent cancer targets. AYPGKF peptide ligand activation of PAR4 induces EGF receptor (EGFR) Tyr-phosphorylation, effectively inhibited by Pc(4-4). The presence of PAR2 and PAR4 in biopsies of aggressive breast and colon cancer tissue specimens is demonstrated. We propose that Pc(4-4) may serve as a powerful drug not only toward PAR-expressing tumors but also for treating EGFR/erbB-expressing tumors in cases of resistance to traditional therapies. Overall, our studies are expected to allocate new targets for cancer therapy. Pc(4-4) may become a promising candidate for future therapeutic cancer treatment.

NAP1L1 promotes the growth of colon cancer by activating HDGF/DDX5.

Colon cancer is a common malignant tumor. However, its pathogenesis still needs further study. In this study, we explored the role of nucleosome assembly protein 1-like 1 (NAP1L1) in colon cancer and its underlying mechanism. Based on analysis of The Cancer Genome Atlas data, we found that NAP1L1 is augmented in colorectal cancer, and the elevated NAP1L1 expression is associated with a poor prognosis in patients with colon cancer. Immunohistochemistry staining results showed that upregulated NAP1L1 protein level is an unfavorable factor that stimulates colon cancer progression. To further investigate the role of NAP1L1 in colon cancer, we established a colon cancer cell line with NAP1L1 knockdown, and found that repressing NAP1L1 expression in colon cancer cells markedly reduces cell proliferation in vivo and in vitro by MTT assay, colony formation, EdU incorporation, and subcutaneous tumorigenesis in nude mice. Furthermore, we found that NAP1L1 binds to HDGF, recruits DDX5, and induces β-catenin/CCND1 signaling, which promotes colon cancer cell proliferation. Finally, transfection with HDGF or DDX5restores cell growth in NAP1L1-knockdown colon cancer cells by upregulating DDX5/β-catenin/CCND1 signaling. Our study demonstrates that NAP1L1 functions as a potential oncogene that promotes colon cancer tumorigenesis by binding to HDGF, which stimulates DDX5/β-catenin/CCND1 signaling.

Oxobedfordia acid reduces colon cancer cell viability through apoptosis induction and inhibits colon cancer growth in mice model

Purpose: Colon cancer is amongst the most commonly diagnosed carcinoma globally and ranks 3rd highest of all the kinds of tumors. In the present study effect of oxobedfordia acid on colon cancer cell viability and colorectal tumor growth in vivo was investigated.Methods: Cytotoxicity of oxobedfordia acid in SW480, HCT116, and FHC cells was evaluated by MTT assay. Colon cancer in the mice was induced by implanting subcutaneously 2 x 106 HT-29 cells/mouse in the right flank. Various parameters, including cell viability, tumor growth and expression levels of cancer factors, were also assessed.Results: Treatment with oxobedfordia acid significantly reduced viability in SW480 and HCT116 cells (p < 0.05). Furthermore, oxobedfordia acid caused increased miR-331-3p levels in cells. Moreover, oxobedfordia acid caused a significant reduction in NRP2 expression and increased apoptosis induction in SW480 and HCT116 cells. Oxobedfordia acid treatment for 48 h significantly increased p53 and p-c- Jun levels, but reduced Bcl-2 expression in cells (p < 0.05). In the mouse model of colon cancer, oxobedfordia acid significantly retarded tumor growth. Furthermore, in oxobedfordia acid-treated mice, expression of miR-331-3p was elevated while NRP2 level was lowered when compared with control group (p < 0.05).Conclusion: Oxobedfordia acid treatment suppresses colon cancer cell viability and inhibits tumor growth in mice through enhancement of miR-331-3p and reduction in NRP2 expression. Hence, oxobedfordia acid can potentially be developed as an agent for the management of colorectal cancer.

Astragalus mongholicus Bunge and Curcuma aromatica Salisb. inhibits liver metastasis of colon cancer by regulating EMT via the CXCL8/CXCR2 axis and PI3K/AKT/mTOR signaling pathway

BackgroundOne of the most challenging aspects of colon cancer (CC) prognosis and treatment is liver-tropic metastasis. Astragalus mongholicus Bunge—Curcuma aromatica Salisb. (AC) is a typical medication combination for the therapy of many malignancies. Our previous studies found that AC intervention inhibits liver metastasis of colon cancer (LMCC). Nevertheless, the comprehensive anti-metastasis mechanisms of AC have not been uncovered.MethodsIn bioinformatics analysis, RNA-seq data of CC and LMCC patients were collected from TCGA and GEO databases, and differentially expressed genes (DEGs) were identified. The biological processes and signaling pathways involved in DEGs were enriched by GO and KEGG. The protein–protein interaction (PPI) network of DEGs was established and visualized using the Cytocape software, followed by screening Hub genes in the PPI network using Degree value as the criterion. Subsequently, the expression and survival relevance of Hub gene in COAD patients were verified. In the experimental study, the effects of AC on the inhibition of colon cancer growth and liver metastasis were comprehensively evaluated by cellular and animal models. Finally, based on the results of bioinformatics analysis, the possible mechanisms of AC inhibition of colon cancer EMT and liver metastasis were explored by in vivo and in vitro pharmacological experiments.ResultsIn this study, we obtained 2386 DEGs relevant to LMCC from the COAD (colon adenocarcinoma) and GSE38174 datasets. Results of GO gene function and KEGG signaling pathway enrichment analysis suggested that cellular EMT (Epithelial-mesenchymal transition) biological processes, Cytokine-cytokine receptor interaction and PI3K/Akt signaling pathways might be closely related to LMCC mechanism. We then screened for CXCL8, the core hub gene with the highest centrality within the PPI network of DEGs, and discovered that CXCL8 expression was negatively correlated with the prognosis of COAD patients. In vitro and in vivo experimental evidence presented that AC significantly inhibited colon cancer cell proliferation, migration and invasion ability, and suppressed tumor growth and liver metastasis in colon cancer orthotopic transplantation mice models. Concomitantly, AC significantly reduced CXCL8 expression levels in cell supernatants and serum. Moreover, AC reduced the expression and transcription of genes related to the PI3K/AKT pathway while suppressing the EMT process in colon cancer cells and model mice.ConclusionsIn summary, our research predicted the potential targets and pathways of LMCC, and experimentally demonstrated that AC might inhibit the growth and liver metastasis in colon cancer by regulating EMT via the CXCL8/CXCR2 axis and PI3K/AKT/mTOR signaling pathway, which may facilitate the discovery of mechanisms and new therapeutic strategies for LMCC.

Pt3R5G inhibits colon cancer cell proliferation through inducing ferroptosis by down-regulating SLC7A11

AimsColon cancer (CC) is a prevalent malignancy worldwide and is one of the most easily altered cancers by dietary regulation. Petunidin 3-O-[rhamnopyranosyl-(trans-p-coumaroyl)]-5-O-(β-D-glucopyranoside) (Pt3R5G) isolated and purified from Lycium ruthenicum Murray, which exhibits highly efficient antioxidant activity and specific anticancer effects, is the flavonoids compound. We aimed to study the effect of Pt3R5G on CC cells and elucidate the potential underlying mechanisms. Main methodsCell proliferation was measured by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and colony formation assays. Cell cycle, cell apoptosis and reactive oxygen species (ROS) analysis were performed by flow cytometry. RNA-sequencing was performed to elucidate the potential underlying mechanisms. The lipid peroxidation level of cells was detected by malondialdehyde (MDA) assay. The mitochondrial morphology of cells was inspected using a transmission electron microscope. Additionally, we overexpressed SLC7A11 to perform rescue experiments. In vivo, xenograft mice assay was performed to verify the effect of Pt3R5G on the growth of colon cancer. Key findingsPt3R5G reduced the cell activity by blocking the cell cycle in G0/G1 phase, inducing the apoptosis and ferroptosis in RKO cells. The overexpressed of SLC7A11, a significantly down-regulated expression gene caused by Pt3R5G, rescued the cell proliferation inhibition and ferroptosis process. Furthermore, Pt3R5G inhibited tumor growth in nude mice. Our study suggests that Pt3R5G inhibits RKO cell proliferation through mainly reducing ferroptosis by down-regulated SLC7A11. SignificanceAs a potential therapeutic drug, Pt3R5G showed efficient anticancer activity through a variety of pathways.

Modulation of POPDC1 Expression by Phenothiazine and Trifluoperazine Suppress Colon Cancer Growth and Migration.

The aim of this study was to investigate the effects of CaM antagonist, PTZ, and TFP on cell proliferation and migration of colon cancer cells and its impact on POPDC protein expression. The 50% inhibitory concentration (IC50) of PTZ and TFP in SW1116, SW480, HCT-15, and COLO205 colon cancer cell lines are measured using MTT. Western blot and immunocytochemistry were used to determine the expression of PCNA, cyclin D1 (CD1), and POPDC proteins. Cell migration was observed using a scratch wound-healing assay. Treatment with PTZ and TFP inhibited colon cancer cells growth in a dose-dependent manner. PTZ and TFP significantly inhibited the activation of proliferation markers, PCNA and CD1, and the migration of colon cancer cells. Furthermore, POPDC protein was significantly suppressed in all cell types of colon cancer, particularly in SW480. Finally, the CaM antagonist upregulates the POPDC1 expression in colon cancer cells. These findings suggest that CaM antagonists suppress colon cancer cells proliferation via downregulation of CD1 and PCNA. In addition, POPDC protein could be used as a biomarker in colon cancer, and CaM antagonist could be used to regulate POPDC1 expression. This study suggests that targeting POPDC1 with CaM inhibition could be a potential therapeutic strategy for colon cancer treatment.<br />.

A natural halogenated fluoride adenosine analog 5'-fluorodeoxy adenosine induced anticolon cancer activity in vivo and in vitro.

Adenosine (ADO) and its analogs have been introduced into the anticancer clinical trials, especial for the ADO derivatives with fluoride. The biosynthesis of fluorinase produces a fluorine-containing ADO analog 5'-fluorodeoxy adenosine (5'-FDA). The toxicity and application of 5'-FDA has not been evaluated, which limits the application of ADO analogs. In order to study its potential mechanism, we carried out the following experiments. In our research, 5'-FDA displayed good antitumor activity in colon cancer cells and two colon cancer models. As a result, 5'-FDA concentration-dependently inhibited the proliferation, migration, and invasion in colon cancer cells through its proapoptosis and cell cycle arrest pathway. Furthermore, 5'-FDA inhibited the growth of colon cancer and its pulmonary metastasis in CT26 inbred mice without affecting their body weight. It was found that 5'-FDA remarkably increased the protein levels of Caspase 3 and cleaved-Caspase 9 and decreased Cyclin A2 and CDK2 via the regulation of p53 signaling pathway, and increased the protein levels of Caspase 8 and cleaved-Caspase 8 which participated in apoptosis pathway. All in all, 5'-FDA displayed excellent therapeutic effects on colon cancer and its pulmonary metastasis. We believed that our study provided a theoretical basis for further preclinical research of 5'-FDA in the treatment of cancer.

Long non-coding RNA LBX2-AS1 predicts poor survival of colon cancer patients and promotes its progression via regulating miR-627-5p/RAC1/PI3K/AKT pathway.

Colon cancer is one of the most prevalent malignant tumors across the world. Increasing studies have demonstrated that long non-coding RNAs (lncRNAs) take part in colon cancer development. Our study intends to explore the expression characteristics of LBX2-AS1, a novel lncRNA, in colon cancer and its underlying mechanisms. The results illustrated that LBX2-AS1 level was substantially increased in colon cancer tissues and was obviously correlated with the tumor volume and early distant metastasis of patients. Besides, overexpression of LBX2-AS1 remarkably boosted growth, proliferation, and metastasis and restrained apoptosis in colon cancer cells, whereas LBX2-AS1 knockdown produced the opposite effect. On the other hand, miR-627-5p, down-regulated in colon cancer tissues, was negatively associated with LBX2-AS1 expression. Functional experiments showed that miR-627-5p suppressed colon cancer growth. Mechanistically, LBX2-AS1, as an endogenous competitive RNA, targeted miR-627-5p and restrained its expression, while miR-627-5p targeted and negatively regulated the RAC1/PI3K/AKT axis. Collectively, this study has revealed that LBX2-AS1 is a poor prognostic factor of colon cancer and can regulate colon cancer progression by regulating the miR-627-5p/RAC1/PI3K/AKT pathway.