Role In Colorectal Cancer Progression Research Articles

Resveratrol triggers autophagy-related apoptosis to inhibit the progression of colorectal cancer via inhibition of FOXQ1.

Colorectal cancer (CRC) is a significant health problem with elevated mortality rates, prompting intense exploration of its complex molecular mechanisms and innovative therapeutic avenues. Resveratrol (RSV), recognised for its anticancer effects through SIRT1 activation, is a promising candidate for CRC treatment. This study focuses on elucidating RSV's role in CRC progression, particularly its effect on autophagy-related apoptosis. Using bioinformatics, protein imprinting and immunohistochemistry, we established a direct correlation between FOXQ1 and adverse CRC prognosis. Comprehensive in vitro experiments confirmed RSV's ability to promote autophagy-related apoptosis in CRC cells. Plasmids for SIRT1 modulation were used to investigate underlying mechanisms. Molecular docking, glutathione-S-transferase pull-down experiments and immunoprecipitation highlighted RSV's direct activation of SIRT1, resulting in the inhibition of FOXQ1 expression. Downstream interventions identified ATG16L as a crucial autophagic target. In vivo and in vitro studies validated RSV's potential for CRC therapy through the SIRT1/FOXQ1/ATG16L pathway. This study establishes RSV's capacity to enhance autophagy-related cell apoptosis in CRC, positioning RSV as a prospective therapeutic agent for CRC within the SIRT1/FOXQ1/ATG16L pathway.

PPP2CA Inhibition Promotes Ferroptosis Sensitivity Through AMPK/SCD1 Pathway in Colorectal Cancer.

Colorectal cancer (CRC) is a very common malignancy of the digestive system. Despite a variety of treatments including surgery, chemotherapeutic and targeted drugs, the prognosis for patients with CRC is still unsatisfactory and the mortality remains high. Protein phosphorylation plays an essential role in tumorigenesis and progression and is also crucial for protein to act with proper functions. Ferroptosis is found widely involved in various diseases especially tumors as a newly identified programmed cell death. In our study, we aimed at PPP2CA as a prospective target which may play a crucial role in CRC progression. In one hand, knockdown of PPP2CA significantly enhanced the malignant phenotype in HCT116. In the other hand, knockdown of PPP2CA significantly enhanced Erastin-induced ferroptosis as well. Specifically, knockdown of PPP2CA in HCT116 significantly increased the relative level of malondialdehyde (MDA), reactive oxygen species (ROS) and Fe2+, and decreased GSH/GSSG ratio after the treatment of certain concentration of Erastin. Besides, we found that the inhibition of PPP2CA further led to the suppression of SCD1 expression in CRC cells in a AMPK-dependent way. Ultimately, we conclude that PPP2CA may regulate Erastin-induced ferroptosis through AMPK/SCD1 signaling pathway.

Abstract 6967: Role of CXCL7 in colon cancer cell proliferation

Abstract Chemokine (C-X-C motif) ligand 7 (CXCL7) - a protein product of the pro platelet basic protein (PPBP) gene - is a potential biomarker for colorectal cancer (CRC) diagnosis. However, its role in CRC progression is not known. Hence, we examined the role of CXCL7 in colon cancer cell proliferation through enhanced aerobic glycolysis. We first examined the effect of CXCL7 on cellular proliferation and glycolytic flux using human colon cancer (HT-29) cells transfected with CXCL7 or an empty vector as a control. Stable CXCL7- and vector-expressing cells were selected using hygromycin B. In addition, we treated HT-29 cells with CXCL7 obtained from the conditioned media (CM) from CXCL7-transfected HEK-293T cells or CM from vector-transfected (control) cells. CXCL7 expression was confirmed by analyzing PPBP expression using RT-qPCR, and CXCL7 level in the conditioned media was quantified by ELISA. The specificity of CXCL7 actions were examined using a CXCL7 neutralizing antibody (R&D Systems) and an antagonist (SB225002) to C-X-C motif chemokine receptor 2 (CXCR2). Cancer cell proliferation was assessed by measuring DNA synthesis (EdU incorporation). Glycolytic flux was monitored by measuring glucose uptake using a fluorescent derivative of 2-deoxyglucose (2-NBDG), Seahorse glycolysis stress test analysis, lactate accumulation in the cultured cell’s media, and Western blotting for glycolytic enzyme protein expression. To further investigate CXCL7-mediated proliferation, we examined EdU incorporation and colony size in 3D engineered tissues and tumor xenograft growth in nude mice injected with CXCL7- and vector-expressing HT29 cells. The proliferation rate in CXCL7-expressing HT-29 cells and HT-29 cells treated with the CXCL7-CM were significantly higher (1.2-fold and 1.8-fold, respectively) compared to controls (p<0.01). Consistently, the proliferation rate in CXCL7-expressing HT-29 3D engineered tissues was significantly enhanced compared to vector-expressing tissues (p<0.05). Importantly, blocking the CXCL7/CXCR2 axis using a CXCL7 neutralizing antibody and a CXCR2 inhibitor abrogated CXCL7-stimulated proliferation. Lactate levels were two-fold higher in the culture media from both CXCL7-expressing HT-29 cells and HT-29 cells treated with CXCL7-CM compared to the controls (p<0.05). Glucose uptake was also greater in CXCL7-overexpressing cells and CXCL7-CM treated cells compared to vector controls. Data from Seahorse assay and Western blots confirmed that CXCL7-expressing HT-29 cells and HT-29 cells treated with CXCL7-CM have higher glycolytic capacity and increased glycolytic enzymes’ protein expression compared to the controls, respectively. In vivo, CXCL7-expressing HT-29 xenograft tumor weight and PCNA protein levels were 100% and 60% greater, respectively, than vector-expressing tumors (p<0.05). Our study for the first time showed that CXCL7 stimulates colon cancer cell proliferation and enhances aerobic glycolysis. Citation Format: Hadeel Aldhowayan, Jannatul F. Nipa, Lauren Jun, Ifeoluwa Odeniyi, Parker L. Jones, Ramesh Jeganathan, Elizabeth A. Lipke, Michael W. Greene. Role of CXCL7 in colon cancer cell proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6967.

Abstract 1172: Association between CD8+ PD-1+ T cell infiltration levels and improved response to total neoadjuvant therapy in mismatch-repair proficient locally advanced rectal cancer

Abstract Background: The tumor microenvironment plays a major role in colorectal cancer progression, dissemination, and response to therapy. As a mechanism of tumor immunity, CD8+ tumor infiltrating lymphocytes have been shown to express PD-1 in response to clonal neoantigens of tumors. We hypothesized that high levels of CD8+ PD-1+ T cell infiltration prior to treatment initiation may correlate with improved response to total neoadjuvant therapy (TNT) in patients with locally advanced rectal cancer (LARC). Methods: We analyzed untreated endoscopic biopsies from 159 patients diagnosed with stage II (n=25) or III (n=134), mismatch-repair proficient rectal adenocarcinoma. All patients were treated with TNT, consisting of either induction chemotherapy followed by chemoradiation (n=108) or chemoradiation followed by consolidative chemotherapy (n=51). FFPE blocks from each biopsy were sectioned into slides for H&E and immunohistochemistry staining with antibodies for CD8 and PD-1 in a CLIA certified lab. CD8+ and PD-1+ cells were quantified using established protocols from the College of American Pathologists. We evaluated associations between response to TNT and tertiles of intratumoral CD8 and PD-1 expression (low/mid/high). Disease free survival (DFS) from the start of TNT and rate of sustained complete response (CR, either clinical or pathologic) were used as primary endpoints. Results: Median follow-up was 40.3 months. The overall CR rate was 42% and the 5-year DFS rate was 77%. Intratumoral CD8 levels were significantly correlated with improved response rates (56% in the top tertile vs. 27% in the bottom tertile, p=0.003, Fisher’s test) and improved 5-year DFS (92% vs. 67% for the top vs. bottom tertiles, respectively; p=0.006, log-rank test). Patients in the highest tertile of intratumoral PD-1 expression also had improved response (56% vs. 25%, p=0.002) and DFS (88% vs. 67%, p=0.034). CD8 and PD-1 levels were strongly correlated with each other (R=0.72, p<0.001, Spearman correlation). Finally, the 41 patients who met criteria for top tertiles of CD8 and PD-1 expression had higher CR rates (66% vs. 32%, p<0.001) and better 5-year DFS (97% vs. 70%, p=0.002) than the other patients. Conclusions: Higher levels of CD8+ and PD-1+ tumor infiltrating lymphocytes on pre-treatment biopsies are associated with improved response to TNT and disease free survival in LARC patients. Citation Format: Christina Lee, Chin-Tung Chen, Nil Urganci, Fan Wu, Canan Firat, Hannah Williams, Evan Seffar, Parisa Malekzadeh, Walid K. Chatila, Jinru Shia, Julio Garcia-Aguilar, Francisco Sanchez-Vega. Association between CD8+ PD-1+ T cell infiltration levels and improved response to total neoadjuvant therapy in mismatch-repair proficient locally advanced rectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1172.

CircXRN2 accelerates colorectal cancer progression through regulating miR-149-5p/MACC1 axis and EMT

In China, there has been a persistent upward trend in the incidence and mortality rates of colorectal cancer (CRC), with CRC ranking second in incidence and fifth in mortality among all malignant tumors. Although circular RNAs (circRNAs) have been implicated in the progression of various cancers, their specific role in CRC progression remains largely unexplored. The objective of this study was to elucidate the role and underlying mechanisms of circXRN2 in CRC. Differential expression of circXRN2 was identified through whole transcriptome sequencing. The expression levels of circXRN2 and miR-149-5p were quantified in CRC tissues, corresponding adjacent normal tissues, and CRC cell lines using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The stability of circXRN2 was confirmed through RNase R and actinomycin D experiments. The binding interaction between circXRN2 and miR-149-5p was validated through RNA pull-down, RNA immunoprecipitation, and dual-luciferase assays. The biological functions of circXRN2 were assessed through a battery of in vitro experiments, including the CCK-8 assay, EdU assay, scratch assay, Transwell assay, and flow cytometry assay. Additionally, in vivo experiments involving a tumor transplantation model and a liver-lung metastasis model were conducted. The influence of circXRN2 on the expression of epithelial–mesenchymal transition (EMT)-related genes was determined via Western blotting analysis. In CRC tissues and cells, there was an upregulation in the expression levels of both circXRN2 and ENC1, while miR-149-5p exhibited a downregulation in its expression. The overexpression of circXRN2 was found to enhance tumor proliferation and metastasis, as evidenced by results from both in vitro and in vivo experiments. Functionally, circXRN2 exerted its antitumor effect by suppressing cell proliferation, migration, and invasion while also promoting apoptosis. Mechanistically, the dysregulated expression of circXRN2 had an impact on the expression of proteins within the EMT signaling pathway. Our results demonstrated that circXRN2 promoted the proliferation and metastasis of CRC cells through the miR-149-5p/ENC1/EMT axis, suggesting that circXRN2 might serve as a potential therapeutic target and novel biomarker in the progression of CRC.

METTL3-mediated RanGAP1 promotes colorectal cancer progression through the MAPK pathway by recruiting YTHDF1

Ran GTPase activating protein 1 (RanGAP1) has been implicated in various diseases, but its role in colorectal cancer (CRC) progression remains unclear. Using tumor tissues and public databases, we found that RanGAP1 was significantly upregulated in CRC tissues and was associated with poor prognosis of patients. N6-methyladenosine (m6A) was found to play an important role in higher expression of RanGAP1. MeRIP-seq, RIP-qPCR, Luciferase reporter assays and other related experiment elucidated the molecular mechanism underlying m6A modification of RanGAP1. Besides, cell function experiments and xenograft tumor models corroborated the function of RanGAP1 in CRC progression. By RNA-seq and related analysis, RanGAP1 was verified to influent CRC progression via the Mitogen-Activated Protein Kinase (MAPK) signaling pathway. Therefore, N6-methyladenosine modification of RanGAP1 by METTL3/YTHDF1 plays a role in CRC progression through the MAPK pathway and could be a potential biomarker and therapeutic target for CRC.Schematic diagram showed that N6-methyladenosine modification of RanGAP1 promotes CRC progression via the MAPK signaling pathway.

RTEL1 is upregulated in colorectal cancer and promotes tumor progression

As one of the most common cancers worldwide, the incidence of colorectal cancer (CRC) continues to increase. Metastasis is the leading cause of death for this malignant disease. Regulator of telomere elongation helicase 1 (RTEL1) is a key factor that maintains telomere stability and contributes to DNA repair. Recent advances have suggested that RTEL1 exerts other functions through various mechanisms. However, little is known about its role in human cancers, including CRC. In this study, we revealed that the copy number of RTEL1 was significantly higher in CRC tissues, especially in metastatic CRC tissues, than in paired normal tissues, which was associated with increased expression. Increased RTEL1 expression was significantly correlated with CRC progression and poor survival. Functionally, RTEL1 knockdown suppressed the proliferation and metastasis of CRC both in vitro and in vivo. In addition, multiple signalling pathways, including the mitotic cell cycle, DNA repair, and EMT, were potentially regulated by RTEL1. Notably, GPR17 appeared to be a candidate downstream target gene that partially mediated the tumor-promoting effects of RTEL1 in CRC. Altogether, our results indicate that RTEL1 plays a crucial role in CRC progression and appears to be a promising therapeutic target and prognosis for CRC.

Anticancer effect of hUC-MSC-derived exosome-mediated delivery of PMO-miR-146b-5p in colorectal cancer

Antisense oligonucleotide (ASO) is a novel therapeutic platform for targeted cancer therapy. Previously, we have demonstrated that miR-146b-5p plays an important role in colorectal cancer progression. However, a safe and effective strategy for delivery of an ASO to its targeted RNA remains as a major hurdle in translational advances. Human umbilical cord mesenchymal cell (hUC-MSC)–derived exosomes were used as vehicles to deliver an anti-miR-146b-5p ASO (PMO-146b). PMO-146b was assembled onto the surface of exosomes (e) through covalent conjugation to an anchor peptide CP05 (P) that recognized an exosomal surface marker, CD63, forming a complex named ePPMO-146b. After ePPMO-146b treatment, cell proliferation, uptake ability, and migration assays were performed, and epithelial-mesenchymal transition progression was evaluated in vitro. A mouse xenograft model was used to determine the antitumor effect and distribution of ePPMO-146b in vivo. ePPMO-146b was taken up by SW620 cells and effectively inhibited cell proliferation and migration. The conjugate also exerted antitumor efficacy in a xenograft mouse model of colon cancer by systematic administration, where PPMO-146b was enriched in tumor tissue. Our study highlights the potential of hUC-MSC-derived exosomes anchored with PPMO-146b as a novel safe and effective approach for PMO backboned ASO delivery.Graphical Schematic illustration of the preparation of an exosomal anchor peptide (CP05)-PMO that conjugately binds to exosomes from hUC-MSCs (ePPMO-146b) and the antitumor effect of ePPMO-146b in CRC, which occurs through the inhibition of Smad signaling and epithelial–mesenchymal transition.

Oncogene SCARNA12 as a potential diagnostic biomarker for colorectal cancer

Colorectal cancer (CRC) is one of the most common malignant tumors of the digestive system, and represents a severe threat to the life and health of individuals. Increasing evidence supports the role of small nucleolar RNAs (snoRNAs) as critical regulatory gene in cancer development. Small Cajal body-specific RNAs (scaRNAs), a subtype of snoRNAs, are named for their subcellular localization within Cajal bodies. SCARNA12, which located at the intronic region of PHB2 in chromosome 12p13.31 with 270 nucleotides (nt) in length. It has been reported function as a diagnostic marker for cervical cancer. However, its biological functions and molecular mechanisms in CRC have yet to be elucidated. In this study, bioinformatics analysis revealed that SCARNA12 was highly expressed in CRC and positively correlated with poor prognosis in CRC patients. Additionally, SCARNA12 showed upregulated expression in CRC cell lines and clinical CRC tissue samples. Moreover, SCARNA12 overexpression in SW620 cells accelerated cell proliferation, suppressed the apoptosis rate, and enhanced tumorigenesis in vivo. The knockdown of SCARNA12 expression in HCT116 and HT29 cells resulted in contrasting effects. The functioning of SCARNA12 is mechanically independent of its host gene PHB2. Notably, the overexpression of SCARNA12 activated PI3K/AKT pathway in SW620 cells, and the malignancy degree of CRC cells was attenuated after treatment with MK2206 (a specific AKT inhibitor). Our findings demonstrated that SCARNA12 plays an oncogenic role in CRC progression and can be used as a potential diagnostic biomarker for CRC.

CXCL5 and CXCL14, but not CXCL16 as potential biomarkers of colorectal cancer

Experts emphasize that colorectal cancer (CRC) incidence and mortality are increasing. That is why its early detection is of the utmost importance. Patients with cancer diagnosed in earlier stages have a better prognosis and a chance for faster implementation of treatment. Consequently, it is vital to search for new parameters that could be useful in its diagnosis. Therefore, we evaluated the usefulness of CXCL5, CXCL14 and CXCL16 in serum of 115 participants (75 CRC patients and 40 healthy volunteers). Concentrations of all parameters were measured using Luminex. CRP (C-reactive protein) levels were determined by immunoturbidimetry, while levels of classical tumor markers were measured using CMIA (Chemiluminescence Microparticle Immunoassay). Concentrations of CXCL5 were statistically higher in the CRC group when compared to healthy controls. The diagnostic sensitivity, specificity, positive and negative predictive value, and area under the ROC curve (AUC) of CXCL5 and CXCL14 were higher than those of CA 19–9. Obtained results suggest the usefulness of CXCL5 and CXCL16 in the determination of distant metastases and differentiation between TNM (Tumor-Node-Metastasis) stages, as well as the usefulness of CXCL14 and CRP combination in CRC detection (primary or recurrence). However, further studies concerning their role in CRC progression are crucial to confirm and explain their diagnostic utility and clinical application as biomarkers.

LINC01485 contributes to colorectal cancer progression by targeting miR-383-5p/KRT80 axis.

Long non-coding RNAs (lncRNAs) are important in tumorigenesis and the development of multiple malignant human tumors, including colorectal cancer (CRC). We aimed to determine the regulatory mechanism of LINC01485 and its biological function in CRC. We estimated the expression of miR-383-5p, KRT80, and LINC01485 in CRC cells and tissues using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting. The results were confirmed using RNA immunoprecipitation (RIP) and dual-luciferase assays. Binding relationships among miR-383-5p, LINC01485, and KRT80 were assessed. We explored the molecular mechanisms and functions of the LINC01485/miR-383-5p/KRT80 axis using CCK-8 and colony formation assays. Expression of the apoptotic markers Bcl-2 and Bax was quantified by western blotting, and the effects of LINC01485 on tumor development in vivo were investigated using xenograft tumors. Both LINC01485 and KRT80 were upregulated, whereas miR-383-5p was downregulated in CRC cells and tissues. Knockdown of LINC01485 attenuated CRC cell growth and xenograft tumor formation in vivo, whereas LINC01485 enhanced the proliferative capacity of CRC cells but inhibited apoptosis by sponging miR-383-5p to increase KRT80 expression in CRC cells. The regulatory molecular mechanism of the LINC01485/miR-383-5p/KRT80 axis plays a crucial role in CRC progression. Our findings highlight novel pathways and promising biomarkers for diagnostic and therapeutic application to patients with CRC.

Mechanism of hsa-miR-222-3p Targeting Integrin Subunit Beta 3 to Regulate Malignant Behavior of Colorectal Cancer HT29 Cells

Colorectal cancer (CRC) is a prevalent malignancy worldwide, and microRNAs (miRNAs) have been recognized for their significant role in CRC progression and potential as therapeutic targets. This study aimed to investigate the impact of miR-222-3p on CRC cell proliferation, migration, and invasion, along with its target genes. HT29 cells were transfected with mimic-negative control (mimic-NC) or mimic-miR-222-3p, while the control group remained untreated. Cell proliferation, migration, and invasion were assessed using CCK-8 and Transwell assays. qRT-PCR and Western blotting were employed to measure gene mRNA and protein expression, respectively. A luciferase reporter assay verified the binding between miR-222-3p and its downstream target gene ITGB3. The results revealed that enhanced miR-222-3p expression significantly increased HT29 cell proliferation, migration, and invasion. qRT-PCR and Western blotting indicated reduced expression of ITGB3 and E-cadherin, and upregulation of Vimentin and α-SMA by miR-222-3p. The luciferase reporter assay confirmed ITGB3 as a direct target of miR-222-3p. In conclusion, miR-222-3p promotes CRC progression by regulating ITGB3 expression, suggesting its potential as a crucial biomarker and therapeutic target for colorectal cancer.

Identification of AOC3 and LRRC17 as Colonic Fibroblast Activation Markers and Their Potential Roles in Colorectal Cancer Progression.

Accumulation of cancer-associated fibroblasts (CAFs) in the tumor stroma is linked to poor prognosis in colorectal cancer (CRC). CAF-cancer cell interplay, facilitated by secretomes including transforming growth factor-beta 1 (TGF-β1), supports fibroblast activation, drives colorectal carcinogenesis, and contributes to CRC aggressive phenotypes. Although widely used, traditional CAF biomarkers are found to have heterogeneous and non-specific expression. Amine oxidase copper containing 3 (AOC3) and leucine-rich repeat-containing 17 (LRRC17) have been reported to be emerging markers of myofibroblasts. Our objective was to investigate the potential of AOC3 and LRRC17 as biomarkers for fibroblast activation thus predicting their roles in CRC progression. Immunofluorescence (IF) staining of AOC3 and LRRC17 was performed on myofibroblast line (CCD-112CoN), primary fibroblasts from colorectal tumor (CAFs), and adjacent normal tissue (normal fibroblasts-NFs). SW620 (epithelial CRC cell line) was used as a control. Conventional CAF biomarker (alpha-smooth muscle actin - α-SMA) was included in the IF analysis. Fluorescence intensity was compared between groups using ImageJ software. Proliferation and contractility of treated cells were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and collagen gel contraction assays, respectively. Fibroblast contraction under TGF-β1 treatment was compared to those treated with complete medium (addition of 10% serum) and serum free (SF) medium. Positive AOC3, LRRC17, and α-SMA expression were observed in colonic fibroblasts, more prominent in CAFs, whereas negative staining was found in SW620. Significant downregulation of AOC3, and upregulations in LRRC17 and α-SMA expression was found in TGF-β1-treated fibroblasts compared to SF medium treatment (p-value<0.05). All fibroblasts exhibited higher proliferation in complete medium and under treatment with conditioned medium from SW620 than SF medium. Significant contraction of NFs was recorded in complete medium and TGF-β1 (p-value<0.01). Our results demonstrate AOC3 and LRRC17 as the potential markers of CAF activation which promote CRC progression.

Perineural invasion in nearby tissue adjacent to colorectal carcinoma with CD166 stem cell marker expression

Abstract Pathological evaluation of colorectal cancer resection samples play a vital role in management and prognosis of postoperative cancer patients. Difficulties exist in the assessment and outcomes of these specimens for therapy protocol. PNI is a perineural invasion associated with increased mortality in many malignancies including colon cancer. In colorectal cancer (CRC) and nearby tissue, PNI evaluation as a potential prognostic indicator with the use of CD 166 stem cell marker remains to be clearly defined for providing a convenient information for future management and prognosis. The incidence and significance of histological neural invasion in nearby tissue was conducted in 52 patients with colorectal carcinoma operated on for the period from June 2017 to June 2020 retrospectively. Tumors were subjected to histopathological and immunohistochemical study (IHC) with CD166 stem cell marker for PNI in tissue adjacent to CRC. Data collected and analyzed, histopathological pictures was obtained and studied. Outcomes showed that neural invasion was expressed by Cd166 stem cell marker as strong and severe in patients with stage B and C in tissues nearby tumor which reveals bad prognostic features. Conclusions: Neurogenesis appeared to have a critical role in colorectal cancer progression. furthermore, current results indicated that neurogenesis functions as an independent predictor of outcomes for therapy protocol.

Knockdown LIMP2 inhibits colorectal cancer cells migration, invasion, and metastasis

Colorectal cancer (CRC) is a common malignancy worldwide nowadays and liver metastasis is the primary cause of death in patients with CRC. Although lysosomal integral membrane protein 2 (LIMP2) has been reported to play important roles in gastric cancer and prostate cancer, its role in CRC remains unclear. The aim of this study was to investigate the function of LIMP2 in CRC invasion and migration, along with the potential underlying molecular mechanisms. We found that LIMP2 levels were higher in CRC tissues compared to adjacent normal tissues. Kaplan-Meier survival analysis showed that high expression of LIMP2 was associated with worse prognosis in CRC patients. Knockdown of LIMP2 significantly inhibited invasion, migration, and wound healing abilities of CRC cells in vitro, and inhibited CRC liver metastasis in vivo. Additionally, LIMP2 knockdown inhibited autophagy in CRC. Therefore, LIMP2 plays an important role in CRC progression. High expression of LIMP2 was associated with worse prognosis in CRC patients. Knockdown LIMP2 can effectively inhibit CRC cell migration and invasion in vitro and prevent liver metastasis in vivo. These findings suggest that LIMP2 may serve as an independent prognostic factor and potential therapeutic target for CRC.

Regulatory role of exosomes in colorectal cancer progression and potential as biomarkers.

Colorectal cancer (CRC) remains an enormous challenge to human health worldwide. Unfortunately, the mechanism underlying CRC progression is not well understood. Mounting evidence has confirmed that exosomes play a vital role in CRC progression, which has attracted extensive attention among researchers. In addition to acting as messengers between CRC cells, exosomes also participate in the CRC immunomodulatory process and reshape immune function. As stable message carriers and liquid biopsy option under development, exosomes are promising biomarkers in the diagnosis or treatment of CRC. In this review we have described and analyzed the biogenesis and release of exosomes and current research on the role of exosomes in immune regulation and metastasis of CRC. Moreover, we have discussed candidate exosomal molecules as potential biomarkers to diagnose CRC, predict CRC progression, or determine CRC chemoresistance, and described the significance of exosomes in the immunotherapy of CRC. This review provides insight to further understand the role of exosomes in CRC progression and identify valuable biomarkers that facilitate the clinical management of CRC patients.

TGM2, HMGA2, FXYD3, and LGALS4 genes as biomarkers in acquired oxaliplatin resistance of human colorectal cancer: A systems biology approach.

Acquired resistance to oxaliplatin is considered as the primary reason for failure in colorectal cancer (CRC) therapy. Identifying the underlying resistance mechanisms may improve CRC treatment. The present study aims to identify the key genes involved in acquired oxaliplatin-resistant in CRC by confirming the oxaliplatin resistance index (OX-RI). To this aim, two public microarray datasets regarding oxaliplatin-resistant CRC cells with different OX-RI, GSE42387, and GSE76092 were downloaded from GEO database to identify differentially expressed genes (DEGs). The results indicated that the OX-RI affects the gene expression pattern significantly. Then, 54 common DEGs in both datasets including 18 up- and 36 down-regulated genes were identified. Protein-protein interaction (PPI) analysis revealed 13 up- (MAGEA6, TGM2, MAGEA4, SCHIP1, ECI2, CD33, AKAP12, MAGEA12, CALD1, WFDC2, VSNL1, HMGA2, and MAGEA2B) and 12 down-regulated (PDZK1IP1, FXYD3, ALDH2, CEACAM6, QPRT, GRB10, TM4SF4, LGALS4, ALDH3A1, USH1C, KCNE3, and CA12) hub genes. In the next step, two novel up-regulated hub genes including ECI2 and SCHIP1 were identified to be related to oxaliplatin resistance. Functional enrichment and pathway analysis indicated that metabolic pathways, proliferation, and epithelial-mesenchymal transition may play dominant roles in CRC progression and oxaliplatin resistance. In the next procedure, two in vitro oxaliplatin-resistant sub-lines including HCT116/OX-R4.3 and HCT116/OX-R10 cells with OX-IR 3.93 and 10.06 were established, respectively. The results indicated the up-regulation of TGM2 and HMGA2 in HCT116/OX-R10 cells with high OX-RI and down-regulation of FXYD3, LGALS4, and ECI2 in both cell types. Based on the results, TGM2, HMGA2, FXYD3, and LGALS4 genes are related to oxaliplatin-resistant CRC and may serve as novel therapeutic targets.

HOTAIR in colorectal cancer: structure, function, and therapeutic potential.

lncRNAs play a vital part in cancer development by regulating gene expression. Among these, the lncRNA HOTAIR has gained considerable attention due to its entanglement in multiple cellular processes, including chromatin remodeling and gene regulation. HOTAIR has a complex structure consisting of multiple domains that interact with various protein complexes and RNA molecules. In colorectal cancer (CRC), HOTAIR expression is upregulated, and its overexpression has been correlated with poor patient prognosis and resistance to chemotherapy. HOTAIR has been found to regulate gene expression and promote cancer growth by interacting with specific miRNAs. In addition, HOTAIR has been implicated in the development of treatment resistance in colorectal cancer. To develop effective treatments, it's important to understand how HOTAIR regulates gene expression. This article discusses HOTAIR's structure, functions, and mechanisms in CRC and its potential as a target for therapy. The author also suggests future research directions to better understand HOTAIR's role in CRC progression and drug resistance.

LKB1 loss promotes colorectal cancer cell metastasis through regulating TNIK expression and actin cytoskeleton remodeling.

Colorectal cancer (CRC) is one of the most common malignant tumors. Approximately 5%-6% of CRC cases are associated with hereditary CRC syndromes, including the Peutz-Jeghers syndrome (PJS). Liver kinase B1 (LKB1), also known as STK11, is the major gene responsible for PJS. LKB1 heterozygotic deficiency is involved in intestinal polyps in mice, while the mechanism of LKB1 in CRC remains elusive. In this study, we generated LKB1 knockout (KO) CRC cell lines by using CRISPR-Cas9. LKB1 KO promoted CRC cell motility in vitro and tumor metastases in vivo. LKB1 attenuated expression of TRAF2 and NCK-interacting protein kinase (TNIK) as accessed by RNA-seq and western blots, and similar suppression was also detected in the tumor tissues of azoxymethane/dextran sodium sulfate-induced intestinal-specific LKB1-KO mice. LKB1 repressed TNIK expression through its kinase activity. Moreover, attenuating TNIK by shRNA inhibited cell migration and invasion of CRC cells. LKB1 loss-induced high metastatic potential of CRC cells was depended on TNIK upregulation. Furthermore, TNIK interacted with ARHGAP29 and further affected actin cytoskeleton remodeling. Taken together, LKB1 deficiency promoted CRC cell metastasis via TNIK upregulation and subsequently mediated cytoskeleton remodeling. These results suggest that LKB1-TNIK axis may play a crucial role in CRC progression.

Targeting RAF Isoforms and Tumor Microenvironments in RAS or BRAF Mutant Colorectal Cancers with SJ-C1044 for Anti-Tumor Activity.

Colorectal cancer (CRC) is a significant global health issue characterized by a high prevalence of KRAS gene mutations. The RAS/MAPK pathway, involving KRAS, plays a crucial role in CRC progression. Although some RAS inhibitors have been approved, their efficacy in CRC is limited. To overcome these limitations, pan-RAF inhibitors targeting A-Raf, B-Raf, and C-Raf have emerged as promising therapeutic strategies. However, resistance to RAF inhibition and the presence of an immunosuppressive tumor microenvironment (TME) pose additional obstacles to effective therapy. Here, we evaluated the potential of a novel pan-RAF inhibitor, SJ-C1044, for targeting mutant KRAS-mediated signaling and inhibiting CRC cell proliferation. Notably, SJ-C1044 also exhibited inhibitory effects on immunokinases, specifically, CSF1R, VEGFR2, and TIE2, which play crucial roles in immune suppression. SJ-C1044 demonstrated potent antitumor activity in xenograft models of CRC harboring KRAS or BRAF mutations. Importantly, treatment with SJ-C1044 resulted in increased infiltration of T cells and reduced presence of tumor-associated macrophages and regulatory T cells within the TME. Thus, SJ-C1044 shows immunomodulatory potential and the ability to enhance antitumor responses. The study underscores the therapeutic potential of SJ-C1044 as a novel pan-RAF inhibitor capable of targeting oncogenic signaling pathways and overcoming immune suppression in CRC.