Invasion Of Colon Cancer Cells Research Articles

Extracellular vesicles carrying miR-193a derived from mesenchymal stem cells impede cell proliferation, migration and invasion of colon cancer by downregulating FAK

MicroRNA (miR) deregulation is frequently seen in colon cancer. In this study, we sought to investigate biological effects of miR-193a on colon cancer and its underlying mechanism. Microarray analysis was conducted to obtain the differentially expressed miRs and their target genes in colon cancer. Bone-marrow derived mesenchymal stem cells (MSCs) and extracellular vesicles (EVs) were obtained. The functional roles of miR-193a and FAK in colon cancer were determined using loss- and gain-function experiments. The cell proliferation, and migration and invasion were evaluated by CCK-8 and Transwell assay respectively. Dual-luciferase reporter assay was performed to confirm the targeting relationship between miR-193a and FAK. Furthermore, in vivo experiment was conducted to test the roles of EV miR-193a in colon cancer growth, followed by determination of PCNA, MMP-2, and MMP-9 protein expression using Western blot analysis. MiR-193a was downregulated, whereas FAK was upregulated in colon cancer. MiR-193a upregulation or FAK downregulation inhibited proliferation, migration and invasion of colon cancer cells. miR-193a could downregulate FAK. Upregulation of EV miR-193a was observed to impede proliferation, migration and invasion of colon cancer cells in vitro and in vivo, accompanied by decreased PCNA, MMP-2, and MMP-9 expression. In summary, EV miR-193a derived from MSCs impeded colon cancer progression by targeting FAK, thus suggesting a new potential strategy for colon cancer treatment.

Rotenone restrains colon cancer cell viability, motility and epithelial‑mesenchymal transition and tumorigenesis in nude mice via the PI3K/AKT pathway.

Rotenone, a natural hydrophobic pesticide, has been reported to display anticancer activity in a variety of cancer cells. However, the mechanism of rotenone on colon cancer (CC) cell migration, invasion and metastasis is still unknown. In the present study, the cytotoxicity of rotenone on CC cells were detected by the Cell Counting Kit-8 assay and confirmed by clone formation assay. The effects of rotenone on CC cell invasion and migration activity were determined in vitro by Transwell invasion and wound healing assays, respectively. In addition, to reveal whether rotenone affected the epithelial-mesenchymal-transition (EMT) process, reverse transcription-quantitative PCR, western blotting and immunofluorescence assays were used to detect the expression of EMT markers. The expression levels of the key markers of the PI3K/AKT pathway after rotenone treatment alone or in combination with a PI3K/AKT signaling activator in CC were also detected by western blotting. Finally, the in vivo anti-tumor effects of rotenone were evaluated in a subcutaneous xenotransplant tumor model treated with an intraperitoneal injection of rotenone. The results of the present study demonstrated that rotenone treatment induced CC cell cytotoxicity and greater effects were observed with increasing concentrations and inhibited cell proliferation compared with untreated cells. In vitro cell function assays revealed that rotenone inhibited CC cell migration, invasion and EMT compared with untreated cells. Mechanically, the phosphorylation levels of AKT and mTOR were downregulated in rotenone-treated CC cells compared with untreated cells. Additionally, AKT and mTOR phosphorylation levels were increased by the PI3K/AKT signaling activator insulin-like growth factor 1 (IGF-1), which was reversed by rotenone treatment. The cell function assays confirmed that the IGF-1-activated cell proliferation, migration and invasion were decreased by rotenone treatment. These results indicated that rotenone affected CC cell proliferation and metastatic capabilities by inhibiting the PI3K/AKT/mTOR signaling pathway. In addition, rotenone inhibited tumor growth and metastatic capability of CC, which was confirmed in a xenograft mouse model. In conclusion, the present study revealed that rotenone inhibited CC cell viability, motility, EMT and metastasis in vitro and in vivo by inhibiting the PI3K/AKT/mTOR signaling pathway.

Mechanism of miR-98 inhibiting tumor proliferation and invasion by targeting IGF1R in diabetic patients combined with colon cancer.

Expression level of miR-98 in diabetic colon cancer (CRC) tissues and the regulation mechanism of colon cancer cell proliferation and invasion ability were studied. Forty patients with type 2 diabetes mellitus complicated with colon cancer, 40 colon cancer patients, and 40 patients with diabetic colonoscopy were enrolled between January 2017 and January 2018. Real-time quantitative PCR was used to detect the expression level of miR-98. After SW480 cells were transfected with miR-98 mimics or control simulants, the proliferation of cancer cells was detected by MTT assay, and the invasion ability of cancer cells was detected by Transwell cell invasion assay. The dual luciferase assay was used to detect the binding relationship between miR-98 and IGF1R. Western blot analysis was used to detect the expression of IGF1R protein in tumor tissues of patients with diabetes mellitus and colon cancer. Compared with diabetic patients, the expression level of miR-98 was decreased in colon cancer patients. Compared with tumor tissues of colon cancer patients, the expression level of miR-98 was significantly decreased in diabetic colon cancer tissues. Compared with the commonly cultured colon cancer SW480 cells, the expression level of miR-98 was significantly decreased in SW480 cells cultured under high glucose conditions. Increased expression of miR-98 inhibits colon cancer cell proliferation and invasion. miR-98 can target and bind to IGF1R and inhibit its expression level. IGF1R is upregulated in diabetic colon cancer tissue. miR-98 inhibits proliferation and invasion of diabetic colon cancer by targeting IGF1R. The expression level of miR-98 in diabetic colon cancer tissues is lower than that in colon cancer tissues. miR-98 can inhibit the proliferation and invasion of colon cancer cells by targeting the target gene IGF1R. miR-98 may be a potential biological target for the treatment of patients with diabetes and colon cancer.

Lnc HAGLR Promotes Colon Cancer Progression Through Sponging miR-185-5p and Activating CDK4 and CDK6 in vitro and in vivo.

Background/AimLncRNA plays a key role in tumor progression. HAGLR functions as an oncogene in many cancers. However, the molecular mechanism of HAGLR in colon cancer is still unclear.MethodsqRT-PCR was used to measure the expression of HAGLR, miR-185-5p in colon cancer. The expression of CDK4 and CDK6 was detected by Western blot. CCK-8 assay, EdU staining, transwell and Annexin V-FITC/PI assay were used to analyze the effect of HAGLR and miR-185-5p on cell proliferation, invasion, migration and apoptosis. Bioinformatic analysis and luciferase were used to analyze the target genes of HAGLR and miR-185-5p. Nude mice were used to detect mouse tumor changes.ResultsCompared with normal colon cancer tissues and cells, the expression of HAGLR was increased in colon cancer tissues and cells. In addition, the expression of HAGLR down-regulation inhibited the growth, migration, and invasion of colon cancer cells. MiR-185-5p was reduced in colon cancer, and CDK4 and CDK6 acted as target genes of miR-185-5p to regulate the progress of colon cancer. And CDK4 and CDK6 were predicted as downstream targets of miR-185-5p. Finally, it was demonstrated that HAGLR regulated tumor progression in vivo.ConclusionLnc HAGLR promoted the development of colon cancer by miR-185-5p/CDK4/CDK6 axis, and lnc HAGLR might be potential target for colon cancer.

MiR-151-3p Inhibits Proliferation and Invasion of Colon Cancer Cell by Targeting Close Homolog of L1.

Colorectal cancer (CRC) is one of the most common malignant tumors in the world. Cases of colon cancer have experienced dramatic growth for the past few decades in China, while the rate of rectal cancer descends 3% every year in the West. The purpose of this study is to reveal the potential impact of miR-21-5p on the occurrence process of CRC and its connection with a close homolog of L1 (CHL1). In this study, the expression level of the miR-151-3p was found to be significantly higher in colon adenocarcinoma tissue compared with adjacent normal tissues, while the CHL1 was lower in colon adenocarcinoma tissues. The expression of miR-151-3p was inversely correlated with the expression of CHL-1, as it was confirmed with correlation analysis. miR-151-3p deregulates the expression of CHL1. CHL1 overexpression can restrain the proliferation and invasion of CRC. Tumorigenesis experiments showed that the tumor growth rate of CHL1-OV was significantly reduced in mice, and its effect could be reversed by miR-151-3p mimics. Taken together, our study may provide new insights into the potential mechanisms of progression of CRC, and may provide a theory for targeted drug therapy.

Effects of MIF on proliferation, migration, and STAT1 pathway of colon cancer cells

Abstract Objective This study aimed to investigate how macrophage migration inhibitory factor (MIF) regulates the interaction of signal transducer and activator of transcription 1 (STAT1) with CD74, and affects colon cancer proliferation and invasion. Methods After transfecting MIF small interfering RNA into the SW480 cell line, the expression of STAT1 and CD74 mRNA was detected by qRT-PCR and western blotting. Transwell and MTT assays were performed to detect the colon cancer cell invasion and proliferation ability. Co-immunoprecipitation was used to detect the interaction between CD74 and STAT1 proteins in the treated and control groups. Results The cellular biological assays (MTT and Transwell) showed that the proliferation and invasion ability of colon cancer cells decreased after MIF knockdown; the results showed significant statistical difference (P < 0.05). The results of the co-immunoprecipitation assay suggested that MIF knockdown in colon cancer cells could inhibit the binding of CD74 and STAT1 proteins; statistical difference was observed between the two groups (P < 0.05). Conclusion MIF can increase the proliferation and invasion of colon cancer cells by promoting the combination of CD74 and STAT1.

Epithelial-mesenchymal transition and metastasis of colon cancer cells induced by the FAK pathway in cancer-associated fibroblasts.

ObjectiveThe role and mechanism of tetrathiomolybdate (TM) in cancer-associated fibroblasts (CAFs) in colon cancer using three-dimensional (3D) culture were investigated, and the associations between the focal adhesion kinase (FAK) pathway and epithelial–mesenchymal transition (EMT) in CAFs were explored.MethodsA 3D co-culture model of colon cancer LOVO cells with CAFs and normal fibroblasts (NFs) was established using Matrigel as a scaffold material. The differential expression of LOXL2 (lysyl oxidase-like 2) in the supernatant of CAFs and NFs was determined using ELISA, and expression levels of EMT-related proteins and FAK signaling pathway-related proteins were determined using western blot.ResultsLOXL2 levels secreted by CAFs were higher compared with that secreted by NFs. In the CAF + LOVO group, compared with the LOVO group, E-cadherin expression decreased significantly, while N-cadherin and F-PAK expression increased significantly. TM results were opposite compared with the above results.ConclusionsCAFs stimulate EMT in human colon cancer LOVO cells by secreting LOXL2 to activate the FAK signaling pathway, thereby promoting tumor metastasis. TM inhibited the occurrence of EMT in the CAF-induced colon cancer LOVO cell line, thereby reducing the invasion and metastasis of colon cancer cells.

MiR‑205 suppresses cell migration, invasion and EMT of colon cancer by targeting mouse double minute 4.

Colon cancer is one of the most frequent malignant tumors, and microRNA (miR)-205 is involved in the tumor progression. The present study aimed to explore the effects of miR-205 on human colon cancer and its targeting mechanism. The levels of miR-205 and mouse double minute 4 (MDM4) were determined via reverse transcription-quantitative (RT-q)PCR and western blot analysis. A luciferase activity assay was performed to analyze the association between miR-205 and MDM4. Cell viability, migration and invasion were determined via Cell Counting Kit-8, wound healing and Transwell assays, respectively. The levels of epithelial-mesenchymal transition (EMT)-associated factors were determined by RT-qPCR and western blot analysis. It was identified that MDM4 was overexpressed in colon cancer tissues and cells, and that there was a negative correlation between miR-205 and MDM4 expression in colon cancer. Similarly, miR-205 inhibited MDM4 expression by binding to its 3′untranslated region. in addition, miR-205 directly targeted MDM4, accompanied by suppressed proliferation, migration and invasion of HCT116 cells. EMT processes were suppressed in miR-205-overexpressed cells; upregulation of E-cadherin, and downregulation of N-cadherin, vimentin, matrix metalloproteinase (MMP)2 and MMP9 were observed. Collectively, miR-205 conspicuously depressed the viability, migration, invasion and EMT process of human colon cancer cells via targeting MDM4. miR-205 could be potentially used in the treatment of human colon cancer.

Cholic Acid Stimulates MMP-9 in Human Colon Cancer Cells via Activation of MAPK, AP-1, and NF-κB Activity

Matrix metalloproteinase-9 (MMP-9) plays a crucial role in cell invasion and cancer metastasis. In this study, we showed that cholic acid (CA), a major primary bile acid, can induce MMP-9 expression in colon cancer HT29 and SW620 cells. CA increased reactive oxygen species (ROS) production and also activated phosphorylation of ERK1/2, JNK, and p38 MAPK. Specific inhibitors and mutagenesis studies showed that ERK1/2 and JNK functioned as upstream signals in the activation of AP-1, and p38 MAPK functioned as an upstream signal in the activation of NF-κB. N-acetyl-L-cysteine (NAC, an ROS scavenger) and diphenyleneiodonium chloride (DPI, an NADPH oxidase inhibitor) inhibited CA-induced activation of ERK1/2, JNK, and p38 MAPK, indicating that ROS production by NADPH oxidase could be the furthest upstream signal in MMP-9 expression. Colon cancer cells pretreated with CA showed remarkably enhanced invasiveness. Such enhancement was partially abrogated by MMP-9-neutralizing antibodies. These results demonstrate that CA could induce MMP-9 expression via ROS-dependent ERK1/2, JNK-activated AP-1, and p38-MAPK-activated NF-κB signaling pathways, which in turn stimulate cell invasion in human colon cancer cells.

Rotenone restrains the proliferation, motility and epithelial-mesenchymal transition of colon cancer cells and the tumourigenesis in nude mice via PI3K/AKT pathway.

Rotenone, a toxic rotenoid compound, has anti‐tumour effects on several cancers. This study aims to clarify the effect of rotenone on the proliferation, apoptosis, invasion and migration of colon cancer cells and tumourigenesis in nude mice. The present results show that rotenone significantly inhibited the proliferation, promoted the apoptosis, and suppressed the invasion and migration of colon cancer cells in a dose‐dependent manner. Rotenone inhibited PI3K/AKT pathway in LoVo and SW480 cells in a dose‐dependent manner. In addition, rotenone regulated the proliferation, apoptosis, invasion, migration and EMT of LoVo and SW480 cells through PI3K/AKT pathway. In colon cancer xenograft mice, rotenone inhibited tumour volume and weight in nude mice, inhibited PI3K/AKT pathway and EMT in vivo. Therefore, rotenone inhibited the proliferation, invasion and migration, promoted the apoptosis of colon cancer cells through PI3K/AKT pathway in vitro, and suppressed the tumourigenesis in nude mice in vivo.

SMYD2 facilitates cancer cell malignancy and xenograft tumor development through ERBB2-mediated FUT4 expression in colon cancer.

The aim of this study is to assess the expression levels of SMYD2 in human tissue samples and cells of colon cancer, and further explore the potential mechanisms of SMYD2 in colon cancer progression. Quantitative PCR and Immunohistochemical (IHC) assays were performed to detect SMYD2 expression in 76 tissue samples of colon cancer tissues and the corresponding normal tissues. The potential correlations between SMYD2 expression levels and clinical pathological features were assessed. We further detected the effects of SMYD2 on the proliferation, invasion and apoptosis of colon cancer cells and on ERBB2/FUT4 signaling pathway through Brdu assay, transwell assay and flow cytometry assay, respectively. The potential effects of SMYD2 on tumor growth were explored using an animal model. We demonstrated the possible involvement of SMYD2 in the progression of colon cancer. We found the high expression of SMYD2 in human colon cancer tissues and cells, and found the correlations between SMYD2 expression and the clinicopathological features including vascular invasion (P = 0.007*), TNM stage (P = 0.016*) and lymph node metastasis (P = 0.011*), of patients with colon cancer. Our data further confirmed that SMYD2 affects cell proliferation, invasion, and apoptosis of colon cancer cells via the regulation of ERBB2/FUT4 signaling pathway. We also demonstrated SMYD2 contributed to tumor growth of colon cancer cells in vivo. We investigated the potential involvement of SMYD2 in the progression of colon, and therefore confirmed SMYD2 as a possible therapeutic target for colon cancer.

β-Carotene exerts anti-colon cancer effects by regulating M2 macrophages and activated fibroblasts

The tumor microenvironment (TME), consisting of stromal fibroblasts, immune cells, cancer cells and other cell types, plays a crucial role in cancer progression and metastasis. M2 macrophages and activated fibroblasts (AFs) modulate behavior of cancer cells in the TME. Since nutritional effects on cancer progression, including colorectal cancer (CRC), may be mediated by alterations in the TME, we determined the ability of β-carotene (BC) to mediate anti-cancer effects through regulation of macrophage polarization and fibroblast activation in CRC. The M2 macrophage phenotype was induced by treating U937 cells with phorbol-12-myristate-13-acetate and interleukin (IL)-4. Treatment of these M2 macrophages with BC led to suppression of M2-type macrophage-associated markers and of the IL-6/STAT3 signaling pathway. In separate experiments, AFs were induced by treating CCD-18Co cells with transforming growth factor-β1. BC treatment suppressed expression of fibroblast activation markers. In addition, conditioned media from BC-treated M2 macrophages and AF inhibited cancer stem cell markers, colon cancer cell invasiveness and migration, and the epithelial-mesenchymal transition (EMT). In vivo, BC supplementation inhibited tumor formation and the expression of M2 macrophage markers in an azoxymethane/dextran sodium sulfate-induced colitis-associated CRC mouse model. To our knowledge, the present findings provide the first evidence suggesting that the potential therapeutic effects of BC on CRC are mediated by the inhibition of M2 macrophage polarization and fibroblast activation.

FSTL3 Promotes Tumor Cell Proliferation, Invasion, Survival and Associates with Poor Prognosis in Colorectal Cancer Patients

Follistatin like‐3 (FSTL3) is a potent inhibitor that antagonizes TGF‐β family ligands including activin, myostatin and bone morphogenetic proteins. Though usually a secreted glycoprotein, nuclear FSTL3 expression had been noted in several cell types, suggesting the existence of specific intracellular functions of this protein. Colorectal cancer (CRC) is one of the leading malignant tumors worldwide. Its strong metastatic ability and chemoresistance tendency is a major obstacle in clinical treatment. In large cohort survival analyses, we have found that FSTL3 has a significant prognostic predictive power in colorectal cancer at both RNA and protein level. Immunohistochemistry staining of CRC specimens revealed that patients with high FSTL3 expression are significantly associated with poor survival. Our study further showed that knockdown of FSTL3 inhibited the migration and invasion of colon cancer cells and reduced tumorigenesis in vivo. Conversely, ectopic over‐expression of FSTL3 elicited the opposite effects in CRC cells. In addition, the overexpression of FSTL3 was found to confer the resistance to 5‐fluorouracil in CRC cells. mRNA profiling analyses suggested that FSTL3 drives CRC tumorigenesis through various carcinogenesis‐related pathways. Our results unveil the significance of FSTL3 in the oncogenesis of CRC, with implications for its potential use as a diagnostic or prognostic biomarker and also a candidate for therapeutic target in this disease.Support or Funding InformationThis research was supported by Academia Sinica [AS‐SUMMIT‐108].

Small Nucleolar RNA, C/D Box 16 (SNORD16) Acts as a Potential Prognostic Biomarker in Colon Cancer.

Colon cancer (CC) is considered one of the most common and lethal malignancies occurring both in male and female. Its widespread prevalence demonstrates the need for novel diagnostic and prognostic biomarkers for CC. Emerging evidence has shown that small nucleolar RNAs play critical roles in tumor development. In this study, we investigated the expression profile and functions of SNORD16 in CC. Our data showed that SNORD16, rather than its host gene (RPL4), was upregulated in CC cell lines. Compared to matched adjacent normal tissues, CC tissues showed higher SNORD16 expression levels, and no correlation was found between SNORD16 and RPL4. Patients with high SNORD16 expression levels had a worse prognosis, and multivariate analysis showed the high SNORD16 expression was an independent prognostic factor for CC. In vitro gain- and loss-of-function studies revealed that SNORD16 can promote cell growth, proliferation, migration, and invasion of CC cells by inhibiting apoptosis. These results suggested that SNORD16 has an oncogenic role in CC and might be a novel diagnostic and prognostic biomarker for CC.

Serine/theonine kinase 4 is a potential biomarker for assessment of β‐catenin‐mediated colon cancer prognosis

Colon cancer has highly incident rate in world, and the surgical therapy can cure early stage colorectal cancer patients. But the most difficult is to predict patients’ disease prognosis. STK4 is a one of the Hippo pathway component and was shown to have important role to control the organ size and cell to cell contact inhibition ability and was considered a potential tumor suppressor. However, little is known about the relationship between the expression of STK4 and patient survival. The aim of this study was to investigate prognostic value of STK4 in colon cancer. STK4 expression in normal and tumor tissues from 140 colon cancer patients was examined by immunohistochemistry. The relationship between STK4 expression and clinicopathological factors as well as patient survival was analyzed. Human colon cancer cell lines (H3347and DLD‐1) were used to analyze the effect of STK4 knockdown and overexpression on invasion/migration in vitro. IHC analysis showed STK4 was significantly downregulated in tumor tissues compared to their corresponding non‐tumor part (P< 0.01) and was significantly associated with tumor size (P = 0.003), distal metastasis (P = 0.03), disease recurrence and poor survival (P< 0.005). Univariate and multivariate analysis indicated loss of STK4 expression predicted significantly poor outcome. Knockdown of STK4 promoted, whereas overexpression of STK4 inhibited invasion and migration of human colon cancer cells in vitro. STK4 is a prognosis maker to predict patient survival in colorectal cancer. Loss of STK4 expressed in tissue is correlated with poor prognosis and survival.Support or Funding InformationThis research was supported by Academia Sinica [AS‐SUMMIT‐108].

Long Non-Coding RNA LEF1-AS1 Promotes Migration, Invasion and Metastasis of Colon Cancer Cells Through miR-30-5p/SOX9 Axis.

IntroductionAberrant expression of long non-coding RNAs (lncRNAs) has been implicated in the tumorigenesis and progression of colon cancer. Lymphoid enhancer-binding factor 1 antisense RNA 1 (LEF1-AS1), a highly conserved and newly discovered long non-coding RNA, has been reported to be upregulated and correlated with poor prognosis in colon cancer, but the exact role of it remains uncertain.Materials and MethodsIn our study, the biological functions of LEF1-AS1 in colon cancer were analyzed by cell viability assay, colony formation assay, scratch wound healing assay, transwell cell invasion assay, soft agar assay, luciferase reporter assay, pull down assay, tumor xenograft model and Western blot.ResultsWe found that LEF1-AS1 was upregulated in colon cancer patients and correlated with poor overall survival and recurrent-free survival. Besides, enforced expression of LEF1-AS1 in HT29 and T84 cells promoted migration, invasion, anchorage-independent growth, tumor xenograft formation and lung metastasis, while knockdown of LEF1-AS1 in COLO320 cells suppressed cell migration, invasion, anchorage-independent growth and tumor xenograft formation. In addition, LEF1-AS1 was directly interacted and inversely correlated with miR-30-5p in colon cancer, and SOX9 was a downstream target for miR-30-5p. LEF1-AS1 overexpression increased the expression level of SOX9, and restoration of SOX9 attenuated the effects caused by LEF1-AS1 knockdown in cell migration, invasion, anchorage-independent growth and tumor xenograft formation.ConclusionOur results indicated that LEF1-AS1 promoted migration, invasion and metastasis of colon cancer cells partially through miR-30-5p/SOX9 axis. The oncogenic LEF1-AS1 could be a potential prognostic biomarker for colon cancer.

Effects of propofol on invasion and migration of colon cancer cells and JAK2/STAT3 signaling pathway.

To investigate the effect of propofol on invasion and migration of human colon cancer cell line SW480 and the JAK2/STAT3 pathway. Human colon cancer cell line SW480 was divided into a control group, 3 propofol treatment groups (with 2, 4 and 8 μg/mL propofol treatment, respectively), and a propofol+colivelin group. Lactate dehydrogenase (LDH) activity and cell proliferation was evaluated by detection kit and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) method, respectively. Cell migration and invasion were detected by Transwell assay. Western blotting was performed to detect the protein expression levels of JAK2, p-JAK 2, STAT3 and p-STAT3 in colon cancer cell line SW480. Compared with the control group, the LDH activity was significantly increased in the propofol treatment groups (P<0.05). The cell proliferation, migration, invasion as well as p-JAK2 and p-STAT3 in colon cancer cell line SW480 in the propofol treatment groups were significantly decreased (allP<0.05). Compared with the propofol treatment groups, the p-STAT3 level, proliferation, migration and invasion in the colon cancer cell line SW480 were significantly increased in the propofol+colivelin group (allP<0.05). Propofol can inhibit the proliferation, migration and invasion of human colon cancer cells by inhibiting JAK2/STAT3 signaling pathway.

Norepinephrine‐CREB1‐miR‐373 axis promotes progression of colon cancer

The adrenergic system contributes to the stress‐induced onset and progression of cancer. Adrenergic fibers are the primary source of norepinephrine (NE). The underlying mechanisms involved in NE‐induced colon cancer remain to be understood. In this study, we describe the function and regulatory network of NE in the progression of colon cancer. We demonstrate that NE‐induced phosphorylation of cAMP response element‐binding protein 1 (CREB1) promotes proliferation, migration, and invasion of human colon cancer cells. The downstream effector of NE, CREB1, bound to the promoter of miR‐373 and transcriptionally activated its expression. miR‐373 expression was shown to be necessary for NE‐induced cell proliferation, invasion, and tumor growth. We confirmed that proliferation and invasion of colon cancer cells are regulated in vitro and in vivo by miR‐373 through targeting of the tumor suppressors TIMP2 and APC. Our data suggest that NE promotes colon cancer cell proliferation and metastasis by activating the CREB1–miR‐373 axis. The study of this novel signaling axis may provide mechanistic insights into the neural regulation of colon cancer and help in the design of future clinical studies on stress biology in colorectal cancer.

The function of Piezo1 in colon cancer metastasis and its potential regulatory mechanism

ObjectiveIncreasing evidence has revealed that mechanical stress and elevated mechanical signals promote malignant tumor transformation and metastasis. This study aimed to explore the function of the mechanically activated ion-channel Piezo1 in the colon cancer metastasis and its potential regulatory mechanism.MethodsFirst, we examined the expression levels of Piezo1 and mitochondrial calcium uniporter (MCU) both in colon cancer tissues and assessed the prognostic value of Piezo1 and MCU in a colon cancer cohort (n = 110). Second, functional assays were performed to investigate the effects of Piezo1 and MCU on colon cancer cell migration, invasion, and mitochondrial membrane potential. Third, we analyzed the expression of Piezo1, MCU, and HIF-1α by overexpressing/silencing each other’s expression.ResultsWe found that Piezo1 was up-regulated and MCU was down-regulated in colon cancer tissues. Piezo1 and MCU were both correlated with poor prognosis of patients with colon cancer. Overexpressing Piezo1 and silencing MCU could promote colon cancer cell migration and metastasis, reduce mitochondrial membrane potential, and promote each other’s expression. We also found that HIF-1α was up-regulated in colon cancer tissues. Additionally, silencing Piezo1 inhibited the expression of HIF-1α and VEGF, which was contrary to MCU silencing. Intriguingly, Piezo1-overexpressing cells did not regain their migration behaviors when HIF-1α expression was inhibited, which was accompanied with the re-expression of MCU and VEGF.ConclusionIn our study, Piezo1 is involved in colon cancer cell metastasis. Furthermore, our findings indicated a possible Piezo1-MCU-HIF-1α-VEGF axis, which still need further exploration.

Anticancer Activities of Meroterpenoids Isolated from the Brown Alga Cystoseira usneoides against the Human Colon Cancer Cells HT-29.

Colorectal cancer (CRC) is one of the most common types of cancers and a leading cause of cancer death worldwide. The current treatment for CRC mainly involves surgery, radiotherapy, and chemotherapy. However, due to the side effects and the emergence of drug resistance, the search for new anticancer agents, pharmacologically safe and effective, is needed. In the present study, we have investigated the anticancer effects of eight algal meroterpenoids (AMTs, 1-8) isolated from the brown seaweed Cystoseira usneoides and their underlying mechanisms of action using HT-29, a highly metastatic human colon cancer cell line. All the tested meroterpenoids inhibited the growth of HT-29 malignant cells and were less toxic towards non-cancer colon cells, with the AMTs 1 and 5 exhibiting selectivity indexes of 5.26 and 5.23, respectively. Treatment of HT-29 cells with the AMTs 1, 2, 3, 4, 5, and 7 induced cell cycle arrest in G2/M phase and, in some instances, apoptosis (compounds 2, 3, and 5). Compounds 1-8 also exhibited significant inhibitory effects on the migration and/or invasion of colon cancer cells. Mechanistic analysis demonstrated that the AMTs 1, 2, 5, 6, 7, and 8 reduced phosphorylation levels of extracellular signal-regulated kinase (ERK) and the AMTs 2, 3, 4, 5, 7, and 8 decreased phosphorylation of c-JUN N-terminal kinase (JNK). Moreover, the AMTs 1, 2, 3, 4, 7, and 8 inhibited phosphorylation levels of protein kinase B (AKT) in colon carcinoma cells. These results provide new insights into the mechanisms and functions of the meroterpenoids of C. usneoides, which exhibit an anticancer effect on HT-29 colon cancer cells by inducing cell cycle arrest and apoptosis via the downregulation of ERK/JNK/AKT signaling pathways.