lncRNAs In Colorectal Cancer Research Articles

M6A‑mediated LINC02038 inhibits colorectal cancer progression via regulation of the FAM172A/PI3K/AKT pathway via competitive binding with miR‑552‑5p.

Long noncoding RNAs (lncRNAs) are a type of regulatory molecule with potential roles in the development of several different malignancies. However, the underlying mechanisms of lncRNAs in colorectal cancer (CRC) are incompletely understood. The present study investigated the molecular mechanism of LINC02038 in CRC. LINC02038 expression was decreased in CRC tissues compared to the para‑cancerous tissues and LINC02038 overexpression markedly reduced the proliferation, vitality, migration and invasive ability and greatly accelerated apoptosis of colorectal cancer cells. Bioinformatics examination indicated that LINC02038 may have targeted microRNA (miR)‑552‑5p. RNA immunoprecipitation and luciferase reporter assays showed that LINC02038 served as a sponge for miR‑552‑5p, hindering target gene FAM172A of miR‑552‑5p degradation. Moreover, methylated RNA immunoprecipitation (MeRIP)‑qualitative PCR assays revealed that YTHDF2 could identify and regulate the METTL3‑mediated LINC02038 N6‑methyladenosine (m6A) modification and increase its degradation, thereby promoting CRC progression via the PI3K/AKT pathway. Based on the CRC clinical specimens, it was shown that LINC02038 was negatively associated with lymphatic metastasis and distant metastasis. These results revealed that m6A/LINC02038/miR‑552‑5p/FAM172A may be a novel anti‑tumor axis and LINC02038 may serve as a biomarker and treatment option for colorectal cancer.

Construction and validation of a metabolic-associated lncRNA risk index for predicting colorectal cancer prognosis.

Metabolic reprogramming is one of the most important events in the development of tumors. Similarly, long non-coding RNAs are closely related to the occurrence and development of colorectal cancer (CRC). However, there is still a lack of systematic research on metabolism-related lncRNA in CRC. Expression data of metabolism-related genes and lncRNA were obtained from The Cancer Genome Atlas (TCGA). Hub metabolism-related genes (HMRG) were screened out by differential analysis and univariate Cox analysis; a metabolism-related lncRNA risk index (MRLncRI) was constructed by co-expression analysis, univariate Cox regression analysis, LASSO, and multivariate Cox regression analysis. Survival curves were drawn by the Kaplan-Meier method. The ssGSEA method assessed the tumor microenvironment of the sample, and the IPS assessed the patient's response to immunotherapy. "Oncopredict" assessed patient sensitivity to six common drugs. MRLncRI has excellent predictive ability for CRC prognosis. Based on this, we also constructed a nomogram that is more suitable for clinical applications. Most immune cells and immune-related terms were higher in the high-risk group. IPS scores were higher in the high-risk group. In addition, the high-risk and low-risk groups were sensitive to different drugs. MRLncRI can accurately predict the prognosis of CRC patients, is a promising biomarker, and has guiding significance for the clinical treatment of CRC.

Long noncoding RNA DLGAP1-AS2 promotes tumorigenesis and metastasis by regulating the Trim21/ELOA/LHPP axis in colorectal cancer

BackgroundLong noncoding RNAs (lncRNAs) have driven research focused on their effects as oncogenes or tumor suppressors involved in carcinogenesis. However, the functions and mechanisms of most lncRNAs in colorectal cancer (CRC) remain unclear.MethodsThe expression of DLGAP1-AS2 was assessed by quantitative RT-PCR in multiple CRC cohorts. The impacts of DLGAP1-AS2 on CRC growth and metastasis were evaluated by a series of in vitro and in vivo assays. Furthermore, the underlying mechanism of DLGAP1-AS2 in CRC was revealed by RNA pull down, RNA immunoprecipitation, RNA sequencing, luciferase assays, chromatin immunoprecipitation, and rescue experiments.ResultsWe discovered that DLGAP1-AS2 promoted CRC tumorigenesis and metastasis by physically interacting with Elongin A (ELOA) and inhibiting its protein stability by promoting tripartite motif containing 21 (Trim21)-mediated ubiquitination modification and degradation of ELOA. In particular, we revealed that DLGAP1-AS2 decreases phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) expression by inhibiting ELOA-mediated transcriptional activating of LHPP and thus blocking LHPP-dependent suppression of the AKT signaling pathway. In addition, we also demonstrated that DLGAP1-AS2 was bound and stabilized by cleavage and polyadenylation specificity factor (CPSF2) and cleavage stimulation factor (CSTF3).ConclusionsThe discovery of DLGAP1-AS2, a promising prognostic biomarker, reveals a new dimension into the molecular pathogenesis of CRC and provides a prospective treatment target for this disease.

LncRNAs AC156455.1 and AC104532.2 as Biomarkers for Diagnosis and Prognosis in Colorectal Cancer.

Background There have been countless studies to date assessing specific oncogenic pathways in a range of tumor classes, but the role of N6-methyladenosine- (m6A-) related long noncoding RNAs (lncRNAs) in colorectal cancer (CRC) remains to be defined. Methods We analyzed such m6A-related lncRNAs by conducting analyses of the Pearson correlation with information originating from the databank of The Cancer Genome Atlas (TCGA). The prognostic relevance of these lncRNAs in CRC was then assessed through a series of univariate Cox regression analyses, leading to the identification of two different m6A modification patterns; they are associated with clinical outcomes and have been used to estimate tumor immune microenvironment (TIME) by the CIBERSORT and ESTIMATE algorithms. We tested the expression of m6A-related lncRNAs in twelve pairs of colorectal cancer tissues and adjacent normal tissues from patients by qRT-PCR. Results We discovered the prognostic risk signature composed of six m6A-related lncRNAs based upon TCGA data. When the overall survival of cases in the dataset of TCGA was investigated, the low-risk cases survived longer than the high-risk CRC cases in both the training and testing cohorts. ROC curves further indicated that m6A-related lncRNA prognostic signature (m6A-LPS) can effectively estimate the survival outcomes of patients in both of these cohorts. We found that lncRNAs AC156455.1 and AC104532.2 were upregulated in twelve colorectal cancer tissues compared with adjacent normal tissues using qRT-PCR. Conclusions This data highlights that the lncRNAs AC156455.1 and AC104532.2 in CRC can be used as biomarkers for diagnostics and prognosis in CRC, demonstrating their potential as targets when designing novel immunotherapeutic regimens.

Comprehensive landscape and future perspectives of long noncoding RNAs (lncRNAs) in colorectal cancer (CRC): Based on a bibliometric analysis.

This review aimed to use bibliometric analysis to sort out, analyze and summarize the knowledge foundation and hot topics in the field of long noncoding RNAs (lncRNAs) in colorectal cancer (CRC), and point out future trends to inspire related research and innovation. We used CiteSpace to analyze publication outputs, countries, institutions, authors, journals, references, and keywords. Knowledge foundations, hotspots, and future trends were then depicted. The overall research showed the trend of biomedical-oriented multidisciplinary. Much evidence indicates that lncRNA plays the role of oncogene or tumor suppressor in the occurrence and development of CRC. Besides, many lncRNAs have multiple mechanisms. lncRNAs and metastasis of CRC, lncRNAs and drug resistance of CRC, and the clinical application of lncRNAs in CRC are current research hotspots. Through insight into the development trend of lncRNAs in CRC, this study will help researchers extract hidden valuable information for further research.

Analysis of LINC01314 and miR-96 Expression in Colorectal Cancer Patients via Tissue Microarray-Based Fluorescence In Situ Hybridization.

Methods A tissue microarray (TMA) containing 76 individual colorectal tumor samples and 28 adjacent normal samples was constructed, and the expression levels of LINC01314 and miR-96 were detected by fluorescence in situ hybridization. Results The expression levels of both LINC01314 and miR-96 were upregulated in CRC tissues and were associated with vascular metastasis (p < 0.05). A significantly positive correlation was observed between LINC01314 and miR-96 expression in tumor tissues (p < 0.001, r = 0.870). Dominant expression of LINC01314 was a risk factor for both blood vessel invasion (p < 0.05) and poor 5-year survival (p = 0.001, hazard ratio = 4.144). The Kaplan–Meier analysis indicated that patients with LINC01314-dominant expression exhibited worse 5-year survival rates than those with miR-96-dominant expression (p < 0.05). Conclusion The expression patterns of both LINC01314 and miR-96 may be diagnostic of, and prognostic for, CRC. These findings will facilitate further exploration of the molecular mechanism of lncRNAs in CRC.

Exosome-derived lnc-HOXB8-1:2 induces tumor-associated macrophage infiltration to promote neuroendocrine differentiated colorectal cancer progression by sponging hsa-miR-6825-5p

IntroductionNeuroendocrine differentiation (NED) in colorectal cancer (CRC) cells has been known for decades, and our previous meta-analysis indicated that CRC patients with neuroendocrine differentiation have a lower 5-year survival rate. In recent years, an increasing number of studies have found that exosome-derived long non-coding RNAs (lncRNAs) play important roles in cancer progression and metastasis. However, the functions and mechanism of exosome-derived lncRNAs in CRC with neuroendocrine differentiation are not yet fully clear.Materials and methodsThe clinical significance of NED was assessed in a retrospective study of 105 patients. Next-generation sequencing and bioinformatics analysis were conducted to select lnc-HOXB8-1:2 for further study. Using immunohistochemistry, qRT–PCR, western blot, transwell assay, immunofluorescence assay, fluorescence in situ hybridization assay and dual-luciferase reporter assay, the oncogenic role of exosome-derived lnc-HOXB8-1:2 was determined in CRC with NED. The mechanism underlying the lnc-HOXB8-1:2/hsa-miR-6825-5p/CXCR3 axis was also explored.ResultsNED was a risk factor for the progression and mortality of CRC. lnc-HOXB8-1:2, derived from exosomes secreted by neuroendocrine differentiated colon cancer cells, was identified in our study. The proportion of M2 macrophages and the migration and invasion capacities of tumor-associated macrophages (TAMs) markedly increased after the addition of neuroendocrine differentiated CRC cell-derived exosomes. More excitingly, the expression of lnc-HOXB8-1:2 and the protein level of CXCR3 were also upregulated in TAMs. The lnc-HOXB8-1:2/hsa-miR-6825-5p/CXCR3 axis was predicted via miRanda software and confirmed by the dual-luciferase reporter assay. Furthermore, the increased expression of lnc-HOXB8-1:2 was accompanied by downregulation of hsa-miR-6825-5p expression and upregulation of CXCR3 protein levels. Overexpression of hsa-miR-6825-5p also reduced CXCR3 expression.Conclusionlnc-HOXB8-1:2 in exosomes derived from neuroendocrine differentiated CRC cells acted as a ceRNA competitively binding hsa-miR-6825-5p to upregulate CXCR3 expression and leading to TAM infiltration and M2 polarization, which promotes neuroendocrine differentiated CRC progression.

LncRNA GAS5 Suppresses Colorectal Cancer Progress by Target miR-21/LIFR Axis.

GAS5 is abnormally high in colorectal cancer tissues, which is a specific expression of lncRNA in colorectal cancer (CRC). Nevertheless, its biological function in CRC has not been elucidated. The abnormal high expression of GAS5 in CRC is the specific expression of lncRNA in CRC. The purpose of our study is to explore the effect of GAS5 on CRC and its mechanism. The expression of GAS5 in 53 paired normal and colorectal cancer tissues and colorectal cancer cell lines was detected by real-time PCR. The biological effects of GAS5, miR-21, and LIFR were measured by functional assays, including wound healing, transwell assays, and in vivo assays. We ensured the carcinogenesis role of GAS5 in CRC in the xenograft nude model. The dual-luciferase reporter assay system and chromatin immunoprecipitation method were used for target evaluation and Western blot for verification. GAS5 was significantly decreased in tumor tissues and CRC cells, and the low expression of CAS5 in CRC promoted tumor metastasis and decreased the survival of patients. GAS5 knockdown increases the cell viability, inhibits apoptosis, and promotes migration. Xenografted tumors in nude mice studies showed that GAS5 knockdown promoted tumor growth and caused worse lesions in colorectal. Furthermore, GAS5 increases the expression level of target gene LIFR to promote the apoptosis of CRC cells by binding to miR-21. Our study revealed that a novel pathway about lncRNA GAS5 inhibited the proliferation and metastasis of CRC cells by targeting miR-21/LIFR which provides a new strategy to treat CRC.

Discovery and Validation of Clinically Relevant Long Non-Coding RNAs in Colorectal Cancer.

Simple SummaryRecent efforts in biomedical research have focused on the identification of molecular biomarkers to improve the diagnosis, prognosis and eventually treatment of the most common human diseases worldwide, including cancer. In this context, a large number of studies point to a pivotal role of long non-coding RNAs (lncRNAs) in the pathophysiology of carcinogenesis, suggesting diagnostic or therapeutic potential. However, for most of them, supporting evidence is scarce and often based on a single large-scale analysis. Here, focusing on colorectal cancer (CRC), we present an overview of the main approaches for discovering and validating lncRNA candidate molecules, and provide a curated list of the most promising lncRNAs associated with this malignancy.Colorectal cancer (CRC) is the third most prevalent cancer worldwide, with nearly two million newly diagnosed cases each year. The survival of patients with CRC greatly depends on the cancer stage at the time of diagnosis, with worse prognosis for more advanced cases. Consequently, considerable effort has been directed towards improving population screening programs for early diagnosis and identifying prognostic markers that can better inform treatment strategies. In recent years, long non-coding RNAs (lncRNAs) have been recognized as promising molecules, with diagnostic and prognostic potential in many cancers, including CRC. Although large-scale genome and transcriptome sequencing surveys have identified many lncRNAs that are altered in CRC, most of their roles in disease onset and progression remain poorly understood. Here, we critically review the variety of detection methods and types of supporting evidence for the involvement of lncRNAs in CRC. In addition, we provide a reference catalog that features the most clinically relevant lncRNAs in CRC. These lncRNAs were selected based on recent studies sorted by stringent criteria for both supporting experimental evidence and reproducibility.

A specific upregulated long noncoding RNA in colorectal cancer promotes cancer progression.

Long noncoding RNA (lncRNA) plays a crucial role in the pathogenesis of various diseases, including colorectal cancer (CRC). The gene mutations of adenomatous polyposis coli (APC) were found in most patients with CRC. They function as important inducers of tumorigenesis. Based on our microarray results, we identified a specific upregulated lncRNA in CRC (SURC). Further analysis showed that high SURC expression correlated with poorer disease-free survival and overall survival in patients with CRC. Furthermore, we found that mutated APC genes can promote the transcription of SURC by reducing the degradation of β-catenin protein in CRC. Functional assays revealed that knockdown of SURC impaired CRC cell proliferation, colony formation, cell cycle, and tumor growth. Additionally, SURC promotes CCND2 expression by inhibiting the expression of miR–185-5p in CRC cells. In conclusion, we demonstrate that SURC is a specific upregulated lncRNA in CRC and the SURC/miR–185-5p/CCND2 axis may be targetable for CRC diagnosis and therapy.

LncRNA CRLM1 inhibits apoptosis and promotes metastasis through transcriptional regulation cooperated with hnRNPK in colorectal cancer

BackgroundColorectal liver metastases (CRLM) continue to have a low survival rate. The number of CRLM regulators and clinical indicators remains limited. Long non-coding RNAs (lncRNAs) are a new master regulator of cell invasion and metastasis. However, the function and regulation mechanism of lncRNAs in colorectal cancer (CRC) metastasis are yet unknown.MethodsTo screen and identify CRLM-related lncRNAs, public transcriptome data were used. Gain and loss of function experiments were carried out to investigate the biological activities of lncRNA CRLM1 in vitro and in vivo. RNA sequencing (RNA-seq), chromatin isolation by RNA purification (ChIRP), immunofluorescence (IF), quantitative real-time PCR (qRT-PCR), western blotting, and rescue experiments were performed to explore the molecular mechanism of CRLM1. Moreover, identified the proteins, DNAs, and RNAs that interact with CRLM1.ResultsThe investigation of lncRNA expression dynamics in CRLM, primary CRC, and normal tissues in this work resulted in identifying a series of lncRNAs associated with metastasis, including CRLM1. CRLM1 inhibited apoptosis of CRC cells and promoted liver metastasis in Balb/C nude mice. CRLM1 was weakly associated with the chromatin regions of genes involved in cell adhesion and DNA damage, and this association was bidirectionally correlated with CRLM1-regulated pro-metastatic gene expression. CRLM1 physically interacts with the hnRNPK protein and promotes its nuclear localization. CRLM1 effectively enhances hnRNPK promoter occupancy and co-regulates the expression of a panel of metastatic genes.ConclusionsThe finding of the clinically significant lncRNA CRLM1 in promoting metastasis and regulating gene expression suggests a potential biomarker and target for CRLM therapy.

Integrated Analysis of a Ferroptosis-Related LncRNA Signature for Evaluating the Prognosis of Patients with Colorectal Cancer.

LncRNAs have been well known for their multiple functions in the tumorigenesis, development, and relapse of colorectal cancer (CRC). Accumulating studies demonstrated that the expression of lncRNAs can be regulated by ferroptosis, a biological process that has been revealed to suppress CRC progression. However, the functions and clinical implications of ferroptosis-associated lncRNAs in CRC remain largely unknown. We, herein, aim to construct a prognostic signature with ferroptosis-related lncRNAs for the prognostic estimation of CRC patients. Firstly, we identified the lncRNAs related to ferroptosis based on the RNA-Seq data of CRC from the TCGA database. The univariate and multivariate Cox analyses were then performed to establish a prognostic signature composed of eight ferroptosis-related lncRNAs (AL161729.4, AC010973.2, CCDC144NL-AS1, AC009549.1, LINC01857, AP003555.1, AC099850.3, and AC008494.3). Furthermore, we divided the CRC patients into high- and low-risk groups based on the signature and found the overall survival (OS) of patients in the high-risk group was significantly shorter than that in the low-risk group (p = 3.31 × 10−11). Moreover, the patients in the high-risk groups had shorter recurrence-free survival (RFS) (p = 6.5 × 10−3) and disease-free survival (DFS) (p = 4.27 × 10−4), as well as higher tumor recurrence rate. Additionally, we found that the oncogenic pathways were enriched in the high-risk group, whereas the ferroptosis pathway that probably repressed CRC development was enriched in the low-risk group. In summary, our signature may provide a theoretical foundation for not only accurate judgment for prognosis but also evaluation for recurrence and metastasis in CRC patients.

Long noncoding RNA TNFRSF10A-AS1 promotes colorectal cancer through upregulation of HuR.

BACKGROUNDRecent studies have emphasized the emerging importance of long noncoding RNAs (lncRNAs) in colorectal cancer (CRC). However, the functions and regulatory mechanisms of numerous lncRNAs in CRC have not been fully elucidated.AIMTo explore the functional role and underlying molecular mechanisms of lncRNA TNFRSF10A-AS1 in CRC.METHODSTNFRSF10A-AS1 expression was measured by quantitative real-time polymerase chain reaction in CRC, and the relationship between TNFRSF10A-AS1 levels and the clinicopathological features of CRC patients was analyzed. The effect of TNFRSF10A-AS1 expression on CRC proliferation and metastasis was examined in vitro and in vivo. Mechanistically, we investigated how TNFRSF10A-AS1 is involved in CRC as a competitive endogenous RNA.RESULTSTNFRSF10A-AS1 was expressed at a high level in CRC and the upregulation of TNFRSF10A-AS1 was associated with advanced T grade and tumor size in CRC patients. A functional investigation revealed that TNFRSF10A-AS1 enhanced the proliferation, migration ability and invasion ability of colon cancer cells in vitro and in vivo. A mechanistic analysis demonstrated that TNFRSF10A-AS1 acted as a miR-3121-3p molecular sponge to regulate HuR expression, ultimately promoting colorectal tumorigenesis and progression.CONCLUSIONTNFRSF10A-AS1 exerts a tumor-promoting function through the miR-3121-3p/HuR axis in CRC, indicating that it may be a novel target for CRC therapy.

Cross-Talk Between m6A- and m5C-Related lncRNAs to Construct a Novel Signature and Predict the Immune Landscape of Colorectal Cancer Patients.

BackgroundN6-methyladenosine (m6A) and 5-methylcytosine (m5C) can modify long non-coding RNAs (lncRNAs), thereby affecting tumorigenesis and tumor progression. However, there is a lack of knowledge regarding the potential roles and cross-talk of m6A- and m5C-related lncRNAs in the tumor microenvironment (TME) and their effect on prognosis.MethodsWe systematically evaluated the expression patterns of m6A- and m5C-related lncRNAs in 1358 colorectal cancer (CRC) samples from four datasets. Consensus clustering was conducted to identify molecular subtypes of CRC, and the clinical significance, TME, tumor-infiltrating immune cells (TIICs), and immune checkpoints in the different molecular subtypes were analyzed. Finally, we established a m6A- and m5C-related lncRNA signature and a prognostic nomogram.ResultsWe identified 141 m6A- and m5C-related lncRNAs by co-expression analysis, among which 23 lncRNAs were significantly associated with the overall survival (OS) of CRC patients. Two distinct molecular subtypes (cluster A and cluster B) were identified, and these two distinct molecular subtypes could predict clinicopathological features, prognosis, TME stromal activity, TIICs, immune checkpoints. Next, a m6A- and m5C-related lncRNA signature for predicting OS was constructed, and its predictive capability in CRC patients was validated. We then constructed a highly accurate nomogram for improving the clinical applicability of the signature. Analyses of clinicopathological features, prognosis, TIICs, cancer stem cell (CSC), and drug response revealed significant differences between two risk groups. In addition, we found that patients with a low-risk score exhibited enhanced response to anti-PD-1/L1 immunotherapy. Functional enrichment analysis showed that these lncRNAs related to the high-risk group were involved in the development and progression of CRC.ConclusionsWe conducted a comprehensive analysis of m6A- and m5C-related lncRNAs in CRC and revealed their potential functions in predicting tumor-immune-stromal microenvironment, clinicopathological features, and prognosis, and determined their role in immunotherapy. These findings may improve our understanding of the cross-talk between m6A- and m5C-related lncRNAs in CRC and pave a new road for prognosis assessment and more effective immunotherapy strategies.

Genome-Wide Methylation Profiling of lncRNAs Reveals a Novel Progression-Related and Prognostic Marker for Colorectal Cancer.

Sporadic colorectal cancer (CRC) develops principally through the adenoma-carcinoma sequence. Previous studies revealed that DNA methylation alterations play a significant role in colorectal neoplastic transformation. On the other hand, long noncoding RNAs (lncRNAs) have been identified to be associated with some critical tumorigenic processes of CRC. Accumulating evidence indicates more intricate regulatory relationships between DNA methylation and lncRNAs in CRC. Nevertheless, the methylation alterations of lncRNAs at different stages of colorectal carcinogenesis based on a genome-wide scale remain elusive. Therefore, in this study, we first used an Illumina MethylationEPIC BeadChip (850K array) to identify the methylation status of lncRNAs in 12 pairs of colorectal cancerous and adjacent normal tissues from cohort I, followed by cross-validation with The Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) database. Then, the abnormal hypermethylation of candidate genes in colorectal lesions was successfully confirmed by MassARRAY EpiTYPER in cohort II including 48 CRC patients, and cohort III including 286 CRC patients, 81 advanced adenoma (AA) patients and 81 nonadvanced adenoma (NAA) patients. DLX6-AS1 hypermethylation was detected at all stages of colorectal neoplasms and occurred as early as the NAA stage during colorectal neoplastic progression. The methylation levels were significantly higher in the comparisons of CRC vs. NAA (P < 0.001) and AA vs. NAA (P = 0.004). Moreover, the hypermethylation of DLX6-AS1 promoter was also found in cell-free DNA samples collected from CRC patients as compared to healthy controls (P adj = 0.003). Multivariate Cox proportional hazards regression analysis revealed DLX6-AS1 promoter hypermethylation was independently associated with poorer disease-specific survival (HR = 2.52, 95% CI: 1.35-4.69, P = 0.004) and overall survival (HR = 1.64, 95% CI: 1.02-2.64, P = 0.042) in CRC patients. Finally, a nomogram was constructed and verified by a calibration curve to predict the survival probability of individual CRC patients (C-index: 0.789). Our findings indicate DLX6-AS1 hypermethylation might be an early event during colorectal carcinogenesis and has the potential to be a novel biomarker for CRC progression and prognosis.

ESRG, LINC00518 and PWRN1 are newly-identified deregulated lncRNAs in colorectal cancer

Colorectal cancer is the 2nd leading cause of death in humans because of cancer. This rank of death could be due to the high rate of incidence from one hand, and the lack of sufficient diagnostic and therapeutic approaches from the other hand. Thus, molecular tools have been emerging as the potential biomarker to improve the early diagnosis and therapeutic management that subsequently could lead to the heightened survival rate of colorectal cancer patients. Long non-coding RNA (lncRNAs) have shown promising capabilities to be used in clinics. The profiling methods could identify novel aberrantly expressed lncRNAs in colorectal cancer. We, thus, performed a comprehensive and unbiased approach to shortlist the dysregulated lncRNAs based on the colon adenocarcinoma TCGA data. An unbiased in silico method was used to rank the yet to profiled lncRNAs in colorectal cancer. qPCR was used to measure the expression level of selected lncRNAs. Our results nominated ESRG, LINC00518, PWRN1, and TTTY14 lncRNAs as the top-hit novel lncRNAs with aberrant expression in colon cancer. The qPCR method was used to profile these lncRNAs that showed the up-regulation of ESRG and LINC00518, and down-regulation of TTTY14 in thirty paired colorectal cancer specimens. The statistical analyses demonstrated that ESRG, LINC00518 and PWRN1 could distinguish the tumor from normal samples. Moreover, ESRG showed a negative correlation with the overall survival of patients. These diagnostic and prognostic results suggest that profiling ESRG, LINC00518 and PWRN1 s may have implications in clinics.

LncRNA LOC100507144 acts as a novel regulator of CD44/Nanog/Sox2/miR-302/miR-21 axis in colorectal cancer.

Long noncoding RNAs (lncRNAs) appear as vital regulators and biomarkers in many human cancers. LOC100507144 is a validated lncRNA located in the neighborhood of CD44 in a head-to-head configuration, and its expression and function in cancer cells are still unknown. This research aimed to find out more about the expression and function of this lncRNA in colorectal cancer (CRC). Our expression data represented that the expression of LOC100507144 transcript was substantially higher in tumors with advanced stages, lymph node metastasis, and vascular invasion. Loss-of-function examinations demonstrated that LOC100507144 contributed to CRC cell proliferation by restricting apoptosis, cellular senescence, and promoting cell cycle. Gain-of-function experiments also confirmed these results. Our data illustrated that LOC100507144 enhanced the migration and the epithelial to mesenchymal transition (EMT) of CRC cells, accompanied by the generation of cells with stemness characteristics. Our findings revealed that the knocking-down of LOC100507144 inhibited the expression of crucial stemness factors, including CD44, Nanog, and Sox2, and accordingly resulted in suppressing their targets, miR-302 and miR-21. Overall, the current study's findings for the first time reveal that LOC100507144 could enhance CRC progression and metastasis through regulation of the CD44/Nanog/Sox2/miR-302/miR-21 axis.

SNHG17 promotes colorectal tumorigenesis and metastasis via regulating Trim23-PES1 axis and miR-339-5p-FOSL2-SNHG17 positive feedback loop

BackgroundSmall nucleolar RNA host gene (SNHG) long noncoding RNAs (lncRNAs) are frequently dysregulated in human cancers and involved in tumorigenesis and progression. SNHG17 has been reported as a candidate oncogene in several cancer types, however, its regulatory role in colorectal cancer (CRC) is unclear.MethodsSNHG17 expression in multiple CRC cohorts was assessed by RT-qPCR or bioinformatic analyses. Cell viability was evaluated using Cell Counting Kit-8 (CCK-8) and colony formation assays. Cell mobility and invasiveness were assessed by Transwell assays. Tumor xenograft and metastasis models were applied to confirm the effects of SNHG17 on CRC tumorigenesis and metastasis in vivo. Immunohistochemistry staining was used to measure protein expression in cancer tissues. RNA pull-down, RNA immunoprecipitation, chromatin immunoprecipitation, and dual luciferase assays were used to investigate the molecular mechanism of SNHG17 in CRC.ResultsUsing multiple cohorts, we confirmed that SNHG17 is aberrantly upregulated in CRC and correlated with poor survival. In vitro and in vivo functional assays indicated that SNHG17 facilitates CRC proliferation and metastasis. SNHG17 impedes PES1 degradation by inhibiting Trim23-mediated ubiquitination of PES1. SNHG17 upregulates FOSL2 by sponging miR-339-5p, and FOSL2 transcription activates SNHG17 expression, uncovering a SNHG17-miR-339-5p-FOSL2-SNHG17 positive feedback loop.ConclusionsWe identified SNHG17 as an oncogenic lncRNA in CRC and identified abnormal upregulation of SNHG17 as a prognostic risk factor for CRC. Our mechanistic investigations demonstrated, for the first time, that SNHG17 promotes tumor growth and metastasis through two different regulatory mechanisms, SNHG17-Trim23-PES1 axis and SNHG17-miR-339-5p-FOSL2-SNHG17 positive feedback loop, which may be exploited for CRC therapy.

Lnc-CPLC promotes the progression of colorectal cancer via regulating ZBTB34 by competitively binding miR-4319.

Long noncoding RNAs (lncRNAs) have been considered as regulatory molecules that play crucial roles in diverse biological processes, including the regulation of tumor progression. However, in colorectal cancer (CRC), due to the complex regulatory relationships involved in lncRNAs, the details of the specific mechanism still need to be elucidated. To discover the key regulatory role of lncRNA in CRC, we used bioinformatics analysis methods for preliminary screening. Through the combination of in vitro and in vivo verification, we further comprehensively analyzed the specific regulation of the key gene and the related key lncRNA in CRC. We found that ZBTB34 and lnc-CPLC (CRC progression-associated lncRNA)had a strong correlation, which plays a key role in the regulation of CRC. Furthermore, by exerting the "sponge" function, lnc-CPLC could bind to miR4319 and release its binding to the 3'UTR of ZBTB34 mRNA. Our results reveal the mechanism of the lnc-CPLC/miR-4319/ZBTB34 signal axis in CRC and provide evidence for elucidating the complex molecular mechanisms in tumors.

Identification and Validation of EMT-Related lncRNA Prognostic Signature for Colorectal Cancer.

Background: This study aimed to explore the biological functions and prognostic role of Epithelial-mesenchymal transition (Epithelial-mesenchymal transition)-related lncRNAs in colorectal cancer (CRC). Methods: The Cancer Genome Atlas database was applied to retrieve gene expression data and clinical information. An EMT-related lncRNA risk signature was constructed relying on univariate Cox regression, Least Absolute Shrinkage and Selector Operation (LASSO) and multivariate Cox regression analysis of the EMT-related lncRNA expression data and clinical information. Then, an individualized prognostic prediction model based on the nomogram was developed and the predictive accuracy and discriminative ability of the nomogram were determined by the receiver operating characteristic curve and calibration curve. Finally, a series of analyses, such as functional analysis and unsupervised cluster analysis, were conducted to explore the influence of independent lncRNAs on CRC. Results: A total of 581 patients were enrolled and an eleven-EMT-related lncRNA risk signature was identified relying on the comprehensive analysis of the EMT-related lncRNA expression data and clinical information in the training cohort. Then, risk scores were calculated to divide patients into high and low-risk groups, and the Kaplan-Meier curve analysis showed that low-risk patients tended to have better overall survival (OS). Multivariate Cox regression analysis indicated that the EMT-related lncRNA signature was significantly associated with prognosis. The results were subsequently confirmed in the validation dataset. Then, we constructed and validated a predictive nomogram for overall survival based on the clinical factors and risk signature. Functional characterization confirmed this signature could predict immune-related phenotype and was associated with immune cell infiltration (i.e., macrophages M0, M1, Tregs, CD4 memory resting cells, and neutrophils), tumor mutation burden (TMB). Conclusions: Our study highlighted the value of the 11-EMT-lncRNA signature as a predictor of prognosis and immunotherapeutic response in CRC.