lncRNAs In Colorectal Cancer Research Articles

LncRNA-HMG incites colorectal cancer cells to chemoresistance via repressing p53-mediated ferroptosis

Upon chemotherapy, excessive reactive oxygen species (ROS) often lead to the production of massive lipid peroxides in cancer cells and induce cell death, namely ferroptosis. The elimination of ROS is pivotal for tumor cells to escape from ferroptosis and acquire drug resistance. Nevertheless, the precise functions of long non-coding RNAs (lncRNAs) in ROS metabolism and tumor drug-resistance remain elusive. In this study, we identify LncRNA-HMG as a chemoresistance-related lncRNA in colorectal cancer (CRC) by high-throughput screening. Abnormally high expression of LncRNA-HMG predicts poorer prognosis in CRC patients. Concurrently, we found that LncRNA-HMG protects CRC cells from ferroptosis upon chemotherapy, thus enhancing drug resistance of CRC cells. LncRNA-HMG binds to p53 and facilitates MDM2-mediated degradation of p53. Decreased p53 induces upregulation of SLC7A11 and VKORC1L1, which contribute to increase the supply of reducing agents and eliminate excessive ROS. Consequently, CRC cells escape from ferroptosis and acquire chemoresistance. Importantly, inhibition of LncRNA-HMG by anti-sense oligo (ASO) dramatically sensitizes CRC cells to chemotherapy in patient-derived xenograft (PDX) model. LncRNA-HMG is also a transcriptional target of β-catenin/TCF and activated Wnt signals trigger the marked upregulation of LncRNA-HMG. Collectively, these findings demonstrate that LncRNA-HMG promotes CRC chemoresistance and might be a prognostic or therapeutic target for CRC.

Exploring the interplay of natural products and long non-coding RNAs in colorectal cancer: pathogenesis, diagnosis, and overcoming drug resistance.

Colorectal cancer (CRC) is recognized as one of the most prevalent malignancies, both in terms of incidence and mortality rates. Current research into CRC has shed light on the molecular mechanisms driving its development. Several factors, including lifestyle, environmental influences, genetics, and diet, play significant roles in its pathogenesis. Natural compounds such as curcumin, tanshinone, lycorine, sinomenine, kaempferol, verbascoside, quercetin, berberine, and fisetin have shown great promise in the prevention and treatment of CRC. Research has also highlighted the significance of non-coding RNAs (ncRNAs) as biomarkers and therapeutic targets in CRC. Among these, long non-coding RNAs (lncRNAs) have been found to regulate the transcription of genes involved in cancer. LncRNAs contribute to cancer stem cell (CSC) proliferation, angiogenesis, epithelial-mesenchymal transition (EMT), and chemoresistance. Specific lncRNAs, including GAS5, LNC00337, HOTAIR, TPT1-AS1, cCSC1, BCAR4, TUG1, and Solh2, play crucial roles in these processes. They hold potential as novel biomarkers, detectable in bodily fluids and tissues, and could serve as therapeutic targets due to their involvement in drug resistance and sensitivity. These insights could improve CRC treatment strategies, addressing resistance to chemotherapy and radiotherapy. This review article aims to provide a comprehensive analysis of the current knowledge regarding the effectiveness of natural anti-cancer agents in CRC treatment. Additionally, it offers an in-depth evaluation of lncRNAs in CRC, their role in the disease's progression, and their potential applications in its management.

Long noncoding RNA KCNMA1-AS2 regulates the function of colorectal cancer cells and sponges miR-1227-5p

BackgroundMany long noncoding RNAs (lncRNAs) with altered expression significantly influence colorectal cancer (CRC) progression and behavior. The functions of many lncRNAs in CRC are not clear yet. This study aimed to discover novel lncRNA entities and comprehensively examine and validate their roles and underlying molecular mechanisms in CRC.MethodsTissue samples, both tumourous and non-tumourous, from three CRC patients were submitted for sequencing. Following expression validation in samples from ten patients and four CRC cell lines. The lncRNA KCNMA1-AS2 was synthesized by In-vitro transcription RNA synthesis and the lncRNA was directly transfected into CRC cell lines to overexpress. Functional assays including MTT proliferation assay, Annexin-V/propidium iodide apoptosis assay, wound healing migration assay and cell cycle assays were performed to evaluate the effect of overexpression of KCNMA1-AS2. Furthermore, the binding of KCNMA1-AS2 to miR-1227-5p was confirmed using dual luciferase reporter assays and qPCR analyses. Subsequent bioinformatics analyses identified 58 potential downstream targets of miR-1227-5p across three databases.ResultsIn this study, we identified the lncRNA KCNMA1-AS2, the expression of which was down-regulated consistently in cancer tissues and CRC cell lines compared to non-cancerous tissues. The overexpression of lncRNA KCNMA1-AS2 led to significant reduction in CRC cell proliferation and migration, increase in cell apoptosis, and more cells arrested in S phase. Additionally, the interaction between KCNMA1-AS2 and miR-1227-5p was confirmed through dual luciferase reporter assay and qPCR analysis. It is also putatively predicted that MTHFR and ST8SIA2 may be linked to CRC based on bioinformatics analyses.ConclusionsLncRNA KCNMA1-AS2 exhibited distinct gene expression patterns in both CRC tissue and cell lines, impacting various cellular functions while also acting as a sponge for miR-1227-5p.The findings spotlight lncRNA KCNMA1-AS2 as a potential marker for diagnosis and treatment of CRC.

M6A modification of lncRNA ABHD11-AS1 promotes colorectal cancer progression and inhibits ferroptosis through TRIM21/IGF2BP2/ FOXM1 positive feedback loop

Long non-coding RNA (lncRNA) is closely related to a variety of human cancers, which may provide huge potential biomarkers for cancer diagnosis and treatment. However, the aberrant expression of most lncRNAs in colorectal cancer (CRC) remains elusive. This study aims to explore the clinical significance and potential mechanism of lncRNA ABHD11 antisense RNA 1 (ABHD11-AS1) in the colorectal cancer. Here, we demonstrated that lncRNA ABHD11-AS1 is high-expressed in colorectal cancer (CRC) patients, and strongly related with poor prognosis. Functionally, ABHD11-AS1 suppresses ferroptosis and promotes proliferation and migration in CRC both in vitro and in vivo. Mechanically, lncRNA ABHD11-AS1 interacted with insulin-like growing factor 2 mRNA-binding protein 2 (IGF2BP2) to enhance FOXM1 stability, forming an ABHD11-AS1/FOXM1 positive feedback loop. E3 ligase tripartite motif containing 21 (TRIM21) promotes the degradation of IGF2BP2 via the K48-ubiquitin-lysosome pathway and ABHD11-AS1 promotes the interaction between IGF2BP2 and TRIM21 as scaffold platform. Furthermore, N6 -adenosine-methyltransferase-like 3 (METTL3) upregulated the stabilization of ABHD11-AS1 through the m6A reader IGF2BP2. Our study highlights ABHD11-AS1 as a significant regulator in CRC and it may become a potential target in future CRC treatment.

LncRNA PVT1 facilitates the growth and metastasis of colorectal cancer by sponging with miR-3619-5p to regulate TRIM29 expression.

Colorectal cancer (CRC) is the second most common cause of cancer-related death worldwide. Long noncoding RNA (lncRNA) is involved in many malignant tumors. This study aimed to clarify the role of the lncRNA plasmacytoma variant translocation 1 (PVT1) in CRC growth and metastasis. Differentially expressed lncRNAs in CRC were analyzed using the Cancer Genome Atlas. Gene expression profiling interactive analysis and a comprehensive resource for lncRNAs from cancer arrays databases were used to analyze lncRNA PVT1 expression and CRC prognosis, respectively. Cell counting kit-8, wound healing, colony formation, Transwell, and immunofluorescence assays were used to evaluate CRC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), respectively. Tumor growth and metastasis models were used to explore the PVT1 effect on the growth and metastasis of CRC in vivo. PVT1 was highly expressed in CRC, associated with a poor prognosis of CRC, and showed good diagnostic value. Transfection of sh-PVT1 or pcDNA3.1-PVT1 reduced or increased the proliferation, wound healing rate, colony formation, invasion, and EMT of CRC cells. PVT1 and miR-3619-5p were co-expressed in CRC cytoplasm, and PVT1 acted as a competitive endogenous RNA (ceRNA) by sponging miR-3619-5p to up-regulate tripartite motif containing 29 (TRIM29) expression. MiR-3619-5p overexpression and TRIM29 knockdown reduced proliferation, wound healing rate, invasion, and EMT of CRC cells. However, simultaneous PVT1 and miR-3619-5p overexpression or knockdown of miR-3619-5p and TRIM29 knockdown rescued the malignant phenotype of CRC cells. We first clarified the ceRNA mechanism of PVT1 in CRC, which induced growth and metastasis by sponging with miR-3619-5p to regulate TRIM29.

Cell type specific long non-coding RNA targets identified by integrative analysis of single-cell and bulk colorectal cancer transcriptomes

Long non-coding RNAs (lncRNAs) represent an emerging class of genes which play significant and diverse roles in human cancers. Nevertheless, the functional repertoires of lncRNAs in cancer cell subtypes remains unknown since most studies are focused on protein coding genes. Here, we explored the contribution of lncRNAs in Colorectal Cancer (CRC) heterogeneity. We analyzed 49′436 single-cells from 29 CRC patients and showed that lncRNAs are significantly more cell type specific compared to protein-coding genes. We identified 996 lncRNAs strongly enriched in epithelial cells. Among these, 98 were found to be differentially expressed in tumor samples compared to normal controls, when integrating 270 bulk CRC profiles. We validated the upregulation of two of them (CASC19 and LINC00460) in CRC cell lines and showed their involvement in CRC proliferation by CRISPR-Cas9 knock down experiments. This study highlights a list of novel RNA targets for potential CRC therapeutics, substantiated through experimental validation.

Predictive significance of glycolysis-associated lncRNA profiles in colorectal cancer progression

BackgroundThe Warburg effect is a hallmark characteristic of colorectal cancer (CRC). Despite extensive research, the role of long non-coding RNAs (lncRNAs) in influencing the Warburg effect remains incompletely understood. Our study aims to identify lncRNAs that may modulate the Warburg effect by functioning as competing endogenous RNAs (ceRNAs).MethodsUtilizing bioinformatics approaches, we extracted glycolysis-associated gene data from the Kyoto Encyclopedia of Genes and Genomes (KEGG) and identified 101 glycolysis-related lncRNAs in CRC. We employed Univariable Cox regression, Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis, and Multivariable Cox regression to develop a prognostic model comprising four glycolysis-linked lncRNAs. We then constructed a prognostic nomogram integrating this lncRNA model with other relevant clinical parameters.ResultsThe prognostic efficacy of our four-lncRNA signature and its associated nomogram was validated in both training and validation cohorts. Functional assays demonstrated significant glycolysis and hexokinase II (HK2) inhibition following the silencing of RUNDC3A − AS1, a key lncRNA in our prognostic signature, highlighting its regulatory importance in the Warburg effect.ConclusionsOur research illuminates the critical role of glycolysis-centric lncRNAs in CRC. The developed prognostic model and nomogram underscore the pivotal prognostic and regulatory significance of the lncRNA RUNDC3A − AS1 in the Warburg effect in colorectal cancer.

Exploring the prognostic significance of iron death‑related lncRNAs in colorectal cancer: A systematic review and meta‑analysis.

Colorectal cancer is a significant health challenge globally, with its prognosis associated with the profile of molecular biomarkers. Recently, the role of iron death-associated long non-coding (lnc)RNAs in cancer development has garnered attention; however, their expression patterns and prognostic value in colorectal cancer remain poorly elucidated. The present study aimed to assess the expression levels of iron death-related lncRNAs in colorectal cancer tissues and evaluate their relationship with patient outcomes through a comprehensive meta-analysis. Systematic searches were performed across multiple databases, including PubMed, Embase, Web of Science, Cochrane Library, CNKI, Wanfang and VIP databases, to identify studies relevant to the objective of the present study. Selected studies met predetermined inclusion criteria, from which data were extracted. R software version 4.3.1 was used for the meta-analysis, evaluating the association between iron death-related lncRNAs expression and colorectal cancer prognosis. Publication bias was assessed using funnel plot analysis, and Begg's and Egger's test. A total of 11 studies, including 3,984 patients with colorectal cancer, were included in the present meta-analysis. The results demonstrated a significant association between iron death-related lncRNAs and tumor stage classification [odds ratio (OR)=2.00; 95% confidence interval (CI), 1.77-2.24]. Notably, a significant association was also revealed between iron death-related lncRNAs and T stage classification in colorectal cancer (OR=1.82; 95% CI, 1.50-2.20). Furthermore, a statistically significant association was demonstrated between iron death-related lncRNAs and lymph node metastasis in colorectal cancer (OR=1.31; 95% CI, 1.03-1.66). The findings also highlighted a significant association between iron death-associated lncRNA and distant metastasis in colon cancer (OR=2.04; 95% CI, 1.62-2.56). Moreover, a significant association between iron death-related lncRNAs and risk score in colorectal cancer was revealed (OR=1.75; 95% CI, 1.25-2.46). In conclusion, the findings of the present meta-analysis underscore the potential of high ferroptosis-associated lncRNA expression as an indicator of adverse outcomes in colorectal cancer, suggesting their viability as biomarkers for cancer progression and prognosis. This insight opens potential new avenues for clinical application and further research into colorectal cancer management.

Upregulated lncRNA PRNT promotes progression and oxaliplatin resistance of colorectal cancer cells by regulating HIPK2 transcription.

Colorectal cancer (CRC) is the third most common cancer and a significant cause of cancer-related mortality globally. Resistance to chemotherapy, especially during CRC treatment, leads to reduced effectiveness of drugs and poor patient outcomes. Long noncoding RNAs (lncRNAs) have been implicated in various pathophysiological processes of tumor cells, including chemotherapy resistance, yet the roles of many lncRNAs in CRC remain unclear. To identify and analyze the lncRNAs involved in oxaliplatin resistance in CRC and to understand the underlying molecular mechanisms influencing this resistance. Gene Expression Omnibus datasets GSE42387 and GSE30011 were reanalyzed to identify lncRNAs and mRNAs associated with oxaliplatin resistance. Various bioinformatics tools were employed to elucidate molecular mechanisms. The expression levels of lncRNAs and mRNAs were assessed via quantitative reverse transcription-polymerase chain reaction. Functional assays, including MTT, wound healing, and Transwell, were conducted to investigate the functional implications of lncRNA alterations. Interactions between lncRNAs and transcription factors were examined using RIP and luciferase reporter assays, while Western blotting was used to confirm downstream pathways. Additionally, a xenograft mouse model was utilized to study the in vivo effects of lncRNAs on chemotherapy resistance. LncRNA prion protein testis specific (PRNT) was found to be upregulated in oxaliplatin-resistant CRC cell lines and negatively correlated with homeodomain interacting protein kinase 2 (HIPK2) expression. PRNT was demonstrated to sponge transcription factor zinc finger protein 184 (ZNF184), which in turn could regulate HIPK2 expression. Altered expression of PRNT influenced CRC cell sensitivity to oxaliplatin, with overexpression leading to decreased sensitivity and decreased expression reducing resistance. Both RIP and luciferase reporter assays indicated that ZNF184 and HIPK2 are targets of PRNT. The PRNT/ZNF184/HIPK2 axis was implicated in promoting CRC progression and oxaliplatin resistance both in vitro and in vivo. The study concludes that PRNT is upregulated in oxaliplatin-resistant CRC cells and modulates the expression of HIPK2 by sponging ZNF184. This regulatory mechanism enhances CRC progression and resistance to oxaliplatin, positioning PRNT as a promising therapeutic target for CRC patients undergoing oxaliplatin-based chemotherapy.

Abstract 6211: Clinical and prognostic assessment of the lncRNA ZFAS1-related gene signature in colorectal cancer

Abstract Colorectal cancer (CRC) is one of the leading causes of cancer death with a rapidly rising incidence rate in younger adults. It is projected to be the leading cause of death in adults under 50 years old by 2030. Although progress over the last couple of decades has improved the clinical management of patients affected by CRC, there is a lack of accurate biomarkers to stratify CRC patients. Among several other biomolecules, lncRNAs (long non-coding RNAs) are non-coding transcripts under 200 nucleotides that can regulate gene expression. Furthermore, lncRNAs are important players in oncogenesis and cancer progression and have the potential to be used as reliable biomarkers. Through this study, we explored the clinical relevance of lncRNAs in colorectal cancer. To analyze the distribution of lncRNAs, we utilized de-identified FFPE (formalin-fixed paraffin-embedded) blocks from Augusta University (n = 88). FFPE blocks were sectioned to extract tissue segments and were subsequently stained using H&E (hematoxylin and eosin dyes) to identify the tumor and adjacent normal regions. The quantification of the gene expression was performed using a medium-throughput NanoString platform. Further analyses were performed using clinicopathological features of the institutional cohort and an independent Cancer Genome Atlas (TCGA) dataset. TCGA contains genomic data along with clinical and molecular characterization of over 11,000 samples of various lineages. In the institutional cohort, ZFAS1 showed higher gene expression in the low survival group for stage II and III colorectal cancer patients, while no significant difference was observed in stage I and IV patients. ZFAS1 expression did not significantly correlate with other clinicopathological parameters, including race, alcohol consumption, tobacco consumption, age, grade, and family history of cancer. In an orthogonal TCGA analysis, higher ZFAS1 expression was associated with genomic perturbations, including significantly altered tumor mutational burden (TMB), aneuploidy, fractional genome alteration, and microsatellite instability. Further, a 21-gene signature was developed for prognostication using gene co-expression network analysis. The gene signature was significantly associated with overall and disease-free survival in the TCGA-CRC cohort. Immune deconvolution analysis of the RNA sequencing data revealed that higher expression of the 21-gene signature was associated with increased infiltration of regulatory T cells while being inversely correlated with the overall level of T cells. In conclusion, our study identified the clinicopathological role of ZFAS1 lncRNA and its interaction genes with prognostic significance in colorectal cancer. Further investigation into the therapeutic relevance of the ZFAS1-related gene signature may prove invaluable in improving the clinical outcomes of colorectal cancer patients. Citation Format: Pankaj Kumar Ahluwalia, Tiffanie Leeman, Ashis Mondal, Ashutosh Vashisht, Harmanpreet Singh, Nivin Omar, Kimya Jones, Ravindra Kolhe. Clinical and prognostic assessment of the lncRNA ZFAS1-related gene signature in colorectal 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 6211.

The m6A modification mediated-lncRNA POU6F2-AS1 reprograms fatty acid metabolism and facilitates the growth of colorectal cancer via upregulation of FASN.

Long noncoding RNAs (lncRNAs) have emerged as key players in tumorigenesis and tumour progression. However, the biological functions and potential mechanisms of lncRNAs in colorectal cancer (CRC) are unclear. The novel lncRNA POU6F2-AS1 was identified through bioinformatics analysis, and its expression in CRC patients was verified via qRT-PCR and FISH. In vitro and in vivo experiments, such as BODIPY staining, Oil Red O staining, triglyceride (TAG) assays, and liquid chromatography mass spectrometry (LC-MS) were subsequently performed with CRC specimens and cells to determine the clinical significance, and functional roles of POU6F2-AS1. Biotinylated RNA pull-down, RIP, Me-RIP, ChIP, and patient-derived organoid (PDO) culture assays were performed to confirm the underlying mechanism of POU6F2-AS1. The lncRNA POU6F2-AS1 is markedly upregulated in CRC and associated with adverse clinicopathological features and poor overall survival in CRC patients. Functionally, POU6F2-AS1 promotes the growth and lipogenesis of CRC cells both in vitro and in vivo. Mechanistically, METTL3-induced m6A modification is involved in the upregulation of POU6F2-AS1. Furthermore, upregulated POU6F2-AS1 could tether YBX1 to the FASN promoter to induce transcriptional activation, thus facilitating the growth and lipogenesis of CRC cells. Our data revealed that the upregulation of POU6F2-AS1 plays a critical role in CRC fatty acid metabolism and might provide a novel promising biomarker and therapeutic target for CRC.

BVES-AS1 suppresses the colorectal cancer progression via the miR-1269a/b-SVEP1-PI3K/AKT axis.

Numerous studies have indicated the engagement of long non-coding RNA (lncRNA) in various cancer types, including colorectal cancer (CRC). However, the functional and mechanistic roles of lncRNAs in CRC remain largely elusive. The aim of this study was to explore the function and mechanism of lncRNA BVES-AS1 in CRC. The expression levels of BVES-AS1 were validated in CRC tissues and paired normal samples using quantitative real-time polymerase chain reaction (qPCR) Subsequently, the biological functions of BVES-AS1 in CRC cells were investigated both in vitro and in vivo. Various experimental techniques such as western blot, fluorescence in situ hybridization, RNA-sequencing (RNA-seq), biotin-labeled miRNA pulldown assay, dual-luciferase reporter gene assay, and RNA-protein immunoprecipitation (RIP) assay were employed to elucidate the potential mechanism of BVES-AS1. The findings of this study demonstrated that BVES-AS1 expression was downregulated in CRC tissues compared to normal tissues, and its expression level was associated with tumor infiltration and tumor-nodule-metastasis (TNM) stage. Furthermore, BVES-AS1 was found to suppress CRC cell proliferation, migration and metastasis both in vitro and in vivo. Mechanistically, BVES-AS1 acted as a sponge for miR-1269a and miR-1269b, thereby regulating SVEP1. Additionally, the silencing of SVEP1 activated the PI3K/AKT pathway. These results suggest that BVES-AS1 plays a crucial role in the progression of CRC through the miR-1269a/b-SVEP1-PI3K/AKT axis, providing new insights into the therapeutic strategies for CRC.

LINC01836 Promotes Colorectal Cancer Progression and Functions as ceRNA to Target SLC17A9 by Sponging miR-1226-3p.

Increasing evidence proves that long non-coding RNAs (lncRNAs) play a key role in the occurrence and development of colorectal cancer. However, the function and molecular mechanism of LINC01836 in CRC are still unknown. The differentially expressed lncRNAs in colorectal cancer were obtained from the RNA sequencing data. The effects of LINC01836 on colorectal cancer cells were tested in in vitro experiments. The mechanism of LINC01836 action was investigated through western blot, RNA immunoprecipitation assay and luciferase reporter assay. Moreover, the xenograft mouse model was conducted to examine the effects of LINC01836 in vivo. In this study, we showed that LINC01836 was significantly elevated in colorectal cancer tissues and cells. Elevated LINC01836 expression significantly correlated with larger tumor size, positive lymph node metastasis, distant metastasis, advanced tumor-node-metastasis (TNM) stage, and poor prognosis. Furthermore, decreased expression of LINC01836 repressed proliferation, migration, and invasion in vitro and vivo, and high LINC01836 expression displayed the opposite effect. Further analysis revealed that LINC01836 could regulate the expression of SLC17A9 by competing with miR---1226-3p. Furthermore, down-regulation of LINC01836 or increased expression of miR-1226-3p markedly reversed the effects of SLC17A9 overexpression on colorectal cancer cells. This study showed that LINC01836 regulated the expression of SLC17A9 through sponge miR-1226-3p by acting as a competitive endogenous RNA (ceRNA), promoted the progression of colorectal cancer, and suggested a new prognostic biomarker and potential cancer treatment target for colorectal cancer.

Dysregulated of the FAM138E and CLRN1-AS1 lncRNAs could be diagnosis biomarkers in colorectal cancer

BackgroundColorectal cancer (CRC) is a malignant tumor that is prone to metastasis and seriously affects human health and longevity. Therefore, identifying suitable biomarkers for diagnostic and therapeutic purposes in CRC is a pressing requirement. The development of bioinformatics analysis has led to the introduction of an increasing number of long non-coding RNAs (lncRNAs) as potential biomarkers. MethodsThe Cancer Genome Atlas Program (TCGA) data for CRC were computationally analyzed to identify new and potential lncRNAs that are dysregulated in CRC. Real-time qPCR was conducted to quantitatively measure the expression levels of FAM138E and CLRN1-AS1 lncRNAs. ResultThis approach led us to select FAM138E and CLRN1-AS1 lncRNAs as dysregulated lncRNAs in the TCGA database. We then quantified the expression levels of these lncRNAs, which interestingly showed overexpression of CLRN1-AS1 (P-value<0.0001, Fold change = 1.55) and downregulation of FAM138E (P-value = 0.012, Fold change = 0.028) in tumors compared to normal adjacent tissues. ConclusionThe evaluated associations with prognosis in CRC using data from TCGA database showed that these lncRNAs could be used as diagnostic factors to detect tumors from normal samples. These findings may have implications for the deeper characterization of FAM138E and CLRN1-AS1 lncRNAs in colorectal cancer.

Long non-coding RNAs and JAK/STAT signaling pathway regulation in colorectal cancer development.

Colorectal cancer (CRC) is one of the main fatal cancers. Cell signaling such as Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling substantially influences the process of gene expression and cell growth. Long non-coding RNAs (lncRNAs) play regulatory roles in cell signaling, cell proliferation, and cancer fate. Hence, lncRNAs can be considered biomarkers in cancers. The inhibitory or activating effects of different lncRNAs on the JAK/STAT pathway regulate cancer cell proliferation or tumor suppression. Additionally, lncRNAs regulate immune responses which play a role in immunotherapy. Mechanisms of lncRNAs in CRC via JAK/STAT regulation mainly include cell proliferation, invasion, metastasis, apoptosis, adhesion, and control of inflammation. More profound findings are warranted to specifically target the lncRNAs in terms of activation or suppression in hindering CRC cell proliferation. Here, to understand the lncRNA cross-talk in CRC through the JAK/STAT signaling pathway, we collected the related in vitro and in vivo data. Future insights may pave the way for the development of novel diagnostic tools, therapeutic interventions, and personalized treatment strategies for CRC patients.

SNHG25 promotes colorectal cancer metastasis by regulating MMP2.

LncRNA has been shown to play an important role in tumors, but the functions of most lncRNAs in colorectal cancer is not clear. By analyzing the transcriptome data of tumor tissues and adjacent tissues, we identified the lncRNA profiles that were abnormally expressed in colorectal cancer and selected the abnormally highly expressed lncRNA SNHG25 for further study. The functional assays showed that after knocking down SNHG25, the metastatic ability of colorectal cancer cells was significantly reduced. Western blot and immunofluorescence assays showed that inhibiting SNHG25 would affect the expression of Vimentin and E-Cadherin. In terms of mechanism, the results of RNA pull down assays, RNA immunoprecipitation (RIP) assays and dual luciferase reporter assays showed that SNHG25 could promote MMP2 expression by adsorbing miR-296-3p. In addition, chromatin immunoprecipitation (ChIP) assays and promoter luciferase reporter assays revealed that PAX5 could activate the transcription of SNHG25 in colorectal cancer cells. Our study proved that SNHG25 acts a pro-metastasis role in colorectal cancer, enriching the theory of the functions of lncRNA in colorectal cancer.

The siRNA-mediated knockdown of SNHG4 efficiently induced pro-apoptotic signaling and suppressed metastasis in SW1116 colorectal cancer cell line.

Long non-coding RNAs are broadly dysregulated in disease conditions, especially cancer, and are associated with tumor initiation, invasion, and overall survival. This study aimed to elucidate the expression level of Small Nucleolar RNA Host Gene 4 (SNHG4) lncRNA in colorectal cancer (CRC) and its effect on cell cycle progression, invasion, and death. We evaluated the expression level of SNHG4 in clinical samples, including CRC tissues, adenomatous colorectal polyps (ACP), and their marginals. SNHG4-silenced SW1116 cells were used to evaluate the cell viability, cycle arrest, invasion, and apoptosis using MTT assay, scratching, flow cytometry, and immunoblotting. We also predicted molecular networks related to the SNHG4 involvement in CRC development. Results showed that SNHG4 expresses in cancerous tissues significantly higher than in polyps and marginals. This overexpression discriminated CRC from marginals and ACP with a suitable prognostic potential. Silencing of SNHG4 arrested the cell cycle at S and G2 phases and promoted early apoptosis in SW1116. It affected the active form of MMP2 and prevented cell invasion. Sponging of miRNAs which promotes the choline metabolism is the probable mechanism of SNHG4 involvement in CRC. In conclusion, SNHG4 promotes CRC by dysregulating apoptosis and cell migration, and shows significant prognostic potential for CRC.

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

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

Long noncoding RNA LINC01594 inhibits the CELF6-mediated splicing of oncogenic CD44 variants to promote colorectal cancer metastasis

Long noncoding RNAs (lncRNAs) play critical roles in tumorigenesis and tumor metastasis. However, the underlying mechanisms of lncRNAs in colorectal cancer (CRC) need further exploration. By using data from The Cancer Genome Atlas (TCGA) and GEO databases, we identified a novel CRC-related lncRNA, LINC01594, that is significantly upregulated in CRC and associated with poor prognosis. In vitro and in vivo, gain- and loss-of-function experiments demonstrated that LINC01594 promotes metastasis in CRC. LINC01594 functions as a DNMT1 scaffold, increasing the level of CELF6 promoter methylation. LINC01594 also competitively binds the transcription factor p53, decreasing CELF6 expression. This inhibited the exon skipping of CD44 V4–V7 induced by CELF6. In summary, this study highlights a novel CRC biomarker and therapeutic target, LINC01594, and the findings suggest that the LINC01594-CELF6-CD44 axis might serve as a biomarker and therapeutic target in CRC.

Construction and validation of stemness-related lncRNA pair signature for predicting prognosis in colorectal cancer.

The purpose of this study was to identify a prognostic signature based on stemness-related differentially expressed lncRNAs in colorectal cancer (CRC) and to investigate their potential as biomarkers for diagnosis, prognosis, and therapeutic targets. Stemness-related genes were collected from the TCGA cohort, and 13 differently expressed stemness-related lncRNAs were identified as prognostic factors for CRC using Kaplan-Meier analysis. A risk model was constructed based on the calculated risk score as a novel independent prognostic factor for CRC patients. The study also investigated the association between the risk model and immune checkpoints and m6A differentiation gene expression. qRT-PCR analysis was performed to validate the expression of differentially expressed stemness-related lncRNAs in CRC cell lines compared to normal colon mucosal cell line. The low-risk lncRNAs were associated with higher survival in CRC patients (Kaplan-Meier analysis, P < 0.001). The risk model was a significant independent prognostic factor for CRC patients. Type I INF response was statistically significant between low- and high-risk groups. CD44, CD70, PVR, TNFSF4, BTNL2, CD40, these immune checkpoints were expressed differently between two risk groups. There was a significant difference between m6A differentiation gene expression such as METTL3, METTL14, WTAP, RBM15, ZC3H13, YTHDC2, YTHDF2, ALKBH5. qRT-PCR analysis validated that there were five up-regulated and eight down-regulated differently expressed stemness-related lncRNAs in CRC cell lines compared to the normal colon mucosal cell line. This study suggests that the 13 CRC stemness-related lncRNA signature could become a promising and reliable prognostic factor for colorectal cancer. The risk model based on the calculated risk score may have implications for personalized medicine and targeted therapies for CRC patients. The study also suggests that immune checkpoints and m6A differentiation genes may play important roles in the development and progression of CRC.