Biomarker In Human Colorectal Cancer Research Articles

Multi-omics prognostic signatures of IPO11 mRNA expression and clinical outcomes in colorectal cancer using bioinformatics approaches.

The most prevalent malignant illness of the gastrointestinal system, colorectal cancer, is the third most prevalent cancer in males and the second most prevalent cancer in women. Importin-11 is a protein that acts as a regulator of cancer cell proliferation in colorectal tumours by conveying -catenin to the cell nucleus. However, the IPO11 gene was found to encode a protein called Importin-11, which functions as a nucleus importer for the cell. As a result, preventing -catenin from entering the nucleus requires blocking Importin-11. As a result, we conducted a multi-omics investigation to assess IPO11 gene potential as a therapeutic biomarker for human colorectal cancer (CC). Oncomine, GEPIA2, immunohisto-chemistry, and UALCAN databases were used to analyses the mRNA expression profiles of IPO11 in CC. The investigation has yielded clear evidence of the increase of IPO11 expression in CC subtypes, as indicated by the data acquired. Analysing CC research from the cBioPortal database, the study discovered three new missense mutations in the importin-11 protein sequence at a frequency of 0.00-1.50% copy number changes. Additionally, the Kaplan-Meier plots demonstrated a strong connection concerning IPO11 downregulation and a poorer CC patient survival rate. The co-expressed gene profile of IPO11 was likewise associated with the onset of CC. IPO11 co-expressed gene profile was also linked to CC development. Moreover, the correlation analysis using bc-GenExMiner and the UCSC Xena server identified KIF2A as the most positively co-expressed gene. The study found that KIF2A and its co-expressed genes were involved in a wide variety of cancer progression pathways using the Enrichr database. Cumulatively, this result will not only provide new information about the expression of IPO11 associated with CC progression and patient survival, but could also serve as a therapeutic biomarker for treating CC in a significant and worthwhile manner. The online version contains supplementary material available at 10.1007/s13755-023-00259-2.

Constructing and Analyzing Competing Endogenous RNA Networks Reveal Potential Biomarkers in Human Colorectal Cancer.

The role of the lncRNA-miRNA-mRNA competing endogenous RNA network in human colorectal cancer remains largely unknown, and accurate prognostics still elude us. This study aimed to identify differentially expressed mRNAs and lncRNAs between tumor and normal samples, delineate their interactions and find reliable biomarkers. We downloaded the RNA sequencing profiles and clinical information of 624 CRC patients from The Cancer Genome Atlas database. After expression difference analysis and interaction prediction, we identified 37 miRNAs, 5 lncRNAs, and 93 mRNAs to construct the ceRNA network (|log2 Fold Change| > 1, P-value < 0.05), and assessed relationships between them and clinical characteristics by t-test, Spearman correlation analysis, and Kaplan-Meier curve analysis. Besides, we validated PIGR and CD3D protein expression by immunohistochemistry staining. PIGR and CD3D mRNAs showed a negative correlation with tumor stage and their protein levels were lower in tumor tissues than in normal tissues. By survival analysis, MYC, F2RL2, and GINS2 positively correlated with the overall survival of CRC patients. Our study provides a novel comprehension of lncRNA-related ceRNA network in CRC and candidate molecules that serve as potential biomarkers of tumor stage and patient survival.

Dickkopf 4 Alone and in Combination with Leucyl-tRNA Synthetase as a Good Prognostic Biomarker for Human Colorectal Cancer.

The prognosis of patients with colorectal cancer (CRC) is affected by invasion and metastasis. Leucyl-tRNA synthetase (LARS) was shown to be related to the growth and migration of lung cancer cells. Dickkopf 4 (DKK4) is known as a Wnt/β-catenin pathway inhibitor, and its upregulation was reported in several cancers. However, the clinical significance of LARS and DKK4 in human CRC has not been clearly defined. We investigated the expression of LARS and DKK4 by immunohistochemical staining in tissue microarrays from 642 primary CRC patients and analyzed the relationship between their expression and the clinicopathological characteristics of CRC patients. LARS and DKK4 expressions were not related to gender, age at surgery, histologic grade, size, tumor location, tumor invasion, or metastasis, but LARS expression was significantly correlated with TNM stage, N stage, and lymph node metastasis. DKK4 expression was inversely related to the TNM stage and N stage. Survival analysis demonstrated that the OS and DFS in the LARS high expression group were not different compared to the LARS low expression group. OS and DFS in the DKK4 high expression group were significantly higher than in the DKK4 low expression group. In addition, OS and DFS in the group with the combination of the LARS high/DKK4 low expression were significantly lower than in the LARS high/DKK4 high expression group. The low expression of DKK4 alone can be used as a predictor of relapse in CRC patients. In addition, DKK4 low expression in the case of LARS high expression can be used as a poor prognostic factor in CRC patients. Thus, our findings suggest that DKK4 alone or in combination with LARS at diagnosis may be a useful prognostic factor for CRC.

Circulating circular RNA ADAM9 a potential biomarker for human colorectal cancer

Colorectal cancer (CRC) is the third most common malignancy worldwide. Recently many studies have suggested circular RNAs (circRNAs) with a critical role in biological processes and as a potential biomarker in CRC. In this study, the expression profile of (circADAM9) was evaluated in CRC tissues and cell lines for the first time. qRT-PCR was used to detect circADAM9 (hsa_circ_0001791) expression level based on the 2−ΔΔct method. In addition, the clinical significance of circADAM9 was evaluated by a two-tailed t-test. The receiver operating characteristic curve (ROC) was calculated using Graph Pad Prism 8 statistical software.Furthermore, bioinformatics analysis was performed to predict candidate targeted miRNA. Our result indicated that circADAM9 was upregulated in CRC tissues and cell lines compared to the normal controls. Statistical data showed a correlation between circADAM9 expression and TNM staging (p = 0.01). Notably, the ROC curve showed that circADAM9 could serve as the potential diagnostic marker for CRC, with AUC = 0.77. The sensitivity and specificity were 0.59 and 0.55, respectively (p < 0.0003). In summary, circADAM9 may play an essential role as a diagnostic biomarker for the inspection of CRC patients.

Prognostic and clinicopathological insights of phosphodiesterase 9A gene as novel biomarker in human colorectal cancer

BackgroundPDE9A (Phosphodiesterase 9A) plays an important role in proliferation of cells, their differentiation and apoptosis via intracellular cGMP (cyclic guanosine monophosphate) signaling. The expression pattern of PDE9A is associated with diverse tumors and carcinomas. Therefore, PDE9A could be a prospective candidate as a therapeutic target in different types of carcinoma. The study presented here was designed to carry out the prognostic value as a biomarker of PDE9A in Colorectal cancer (CRC). The present study integrated several cancer databases with in-silico techniques to evaluate the cancer prognosis of CRC.ResultsThe analyses suggested that the expression of PDE9A was significantly down-regulated in CRC tissues than in normal tissues. Moreover, methylation in the DNA promoter region might also manipulate PDE9A gene expression. The Kaplan–Meier curves indicated that high level of expression of PDE9A gene was associated to higher survival in OS, RFS, and DSS in CRC patients. PDE9A demonstrated the highest positive correlation for rectal cancer recurrence with a marker gene CEACAM7. Furtheremore, PDE9A shared consolidated pathways with MAPK14 to induce survival autophagy in CRC cells and showed interaction with GUCY1A2 to drive CRPC.ConclusionsOverall, the prognostic value of PDE9A gene could be used as a potential tumor biomarker for CRC.

GOLM1 Drives Colorectal Cancer Metastasis by Regulating Myeloid-derived Suppressor Cells

Colorectal cancer (CRC) is the most common digestive neoplasms worldwide, metastasis and recurrence still account for the leading cause for the high mortality rate, but the exact mechanisms remain unclear. More and more evidence has indicated that the deregulation of GOLM1 plays a crucial role in cancer progression. Here, we reported a novel role of GOLM1 in promoting CRC metastasis. In this study, the expression of GOLM1 was detected in human CRC cohort. The function of GOLM1 in CRC metastasis was analyzed by in vivo cecum orthotopic model. We found that the expression of GOLM1 was significantly increased in CRC tissues than adjacent nontumor. Overexpression GOLM1 can promote CRC immune escape and metastasis by recruiting of myeloid-derived suppressor cells (MDSCs) at the same time. PF-04136309, a small molecule and specific inhibitor of CCR2 can largely suppressed GOLM1-mediated CRC metastasis. These results suggest that GOLM1 can promote CRC metastasis and is a prognostic biomarker in human CRC.

A novel circular RNA hsa_circ_0060927 may serve as a potential diagnostic biomarker for human colorectal cancer.

CYP24A1 plays a role in strictly regulated vitamin D metabolism pathway and has been nominated as a prognostic biomarker for colorectal cancer (CRC). Increasing evidence suggests that circular RNAs (circRNAs) are involved in cancer initiation and progression; however, their diagnostic values in cancers as the new potential biomarkers are still not fully understood. In the present study, by using quantitative real-time polymerase chain reaction (qRT-PCR), we demonstrated that CYP24A1 and hsa_circ_0060927 were only transcribed in 33 and 25 out of 83 CRC tissues, respectively. In these samples, we demonstrated that CYP24A1 was up-regulated in both linear and circular forms (P<0.05). Furthermore, we showed that CYP24A1and hsa_circ_0060927 transcription were induced after vitamin D treatment in HCT-116 and HT-29 colon cancer cell lines. Importantly, analysis of the ROC curve in expressed samples indicated that CYP24A1 and hsa_circ_0060927 could serve as the potential diagnostic markers of CRC, but due to the fact that these transcripts are not expressed in many samples, the diagnostic role of these transcripts could be rejected. Taken together, for the first time, the results of our study illustrated the expression levels hsa_circ_0060927 in CRC; however, further studies are required to validate the present results.

RNA-Seq Profiling of Serum Exosomal Circular RNAs Reveals Circ-PNN as a Potential Biomarker for Human Colorectal Cancer.

Circular RNAs (circRNAs) are emerging as cardinal areas of focus in the non-coding RNA field. Growing evidences have revealed exosomal circRNAs as potential biomarkers for detection of various cancers. However, the clinical importance of most serum exosomal circRNAs in colorectal cancer (CRC) have rarely been investigated. In this study, we examined the possible clinical application of serum exosomal circRNAs in the diagnosis of CRC. Firstly, we conducted RNA sequencing (RNA-seq) analysis using fifty CRC and fifty healthy control serum samples to identify CRC-related circRNAs. The sequencing data showed 122 differentially expressed circRNAs including 100 up-regulated and 22 down-regulated circRNA transcripts in CRC patients. Then, eight most dysregulated circRNAs were selected for validation by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assay. Validation analysis revealed that the serum exosomal circ-PNN (hsa_circ_0101802) levels were significantly up-regulated in CRC cases compared with those in the healthy control groups. Receiver operating characteristic curve (ROC) analysis suggested that circ-PNN had significant value in CRC diagnosis with areas under the ROC curve (AUC) of 0.855 and 0.826 in the training and validation sets, respectively. We also found that the AUC of serum exosomal circ-PNN for early-stage CRC was 0.854. Finally, a network map based on circ-PNN was constructed to determine its potential miRNA-mRNAs binding. We also demonstrated that the expression of hsa-miR-6833-3P, hsa-let-7i-3p and hsa-miR-1301-3P were negatively correlated with circ-PNN in CRC patients. Collectively, our findings indicated that serum exosomal circ-PNN might be a potential non-invasive biomarker for the detection of CRC and may play a crucial role in the pathogenesis of CRC.

Restoring Treatment Response in Colorectal Cancer Cells by Targeting MACC1-Dependent ABCB1 Expression in Combination Therapy.

Treatment failure of solid cancers, represented by the development of drug resistance in the primary tumor or later outgrowth of drug resistant metastases, is the major cause of death for cancer patients. It represents an urgent clinical need for predictive biomarkers which indicate the success or failure of standard treatment regimens. Besides treatment prediction, interfering with cellular processes associated with drug resistance might improve treatment response by applying combination therapies. Metastasis-associated in colon cancer (MACC) 1 was identified in our group as a prognostic biomarker in human colorectal cancer, and has been established as key player, prognostic, and predictive biomarker for tumor progression and metastasis in a variety of solid cancers. Besides increased cell proliferation and motility, subsequently contributing to growth and metastatic spread of the primary tumor, MACC1 has also been shown to dysregulate apoptosis and is contributing to treatment resistance. Here we report the MACC1 dependent treatment resistance of colorectal cancer (CRC) cells to standard therapeutics like doxorubicin by upregulating ATP-binding cassette subfamily B member 1 (ABCB1) protein. Overexpression of MACC1 in CRC cells increased both its presence on the ABCB1 promoter and its transcriptional activity, resulting in elevated ABCB1 expression and thus treatment resistance to standard therapeutics. In contrast, depleting MACC1 increased intracellular drug concentrations, leading to better treatment response. We already identified the first MACC1 transcriptional inhibitors, such as lovastatin, by high-throughput screening of clinically approved small molecule drugs. These compounds inhibited cell motility in vitro but also restricted metastasis development in xenograft mouse models by reducing MACC1 expression. Here we report, that treating high MACC1 expressing CRC cells with a combination of statins and standard therapeutics increased the rate of cytotoxicity and resulted in higher treatment response.

Plasma Inter-Alpha-Trypsin Inhibitor Heavy Chains H3 and H4 Serve as Novel Diagnostic Biomarkers in Human Colorectal Cancer.

Objective Inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3) and inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4) are heavy chains of protein members belonging to the ITI family, which was associated with inflammation and carcinogenesis. However, the diagnostic value of ITIH3 and ITIH4 in human colorectal cancer (CRC) remains unknown. Methods In total, 101 CRC patients and 156 healthy controls were enrolled. The concentrations of ITIH3 and ITIH4 proteins in plasma samples of participants were assessed using enzyme-linked immunosorbent assay. ITIH3 and ITIH4 expressions in human CRC tissues were additionally assessed via immunohistochemical staining (IHC). Receiver operating characteristic (ROC) was applied to estimate the diagnostic power of the two proteins, and the net reclassification improvement (NRI) was adopted to evaluate the incremental predictive ability of ITIH3/ITIH4 when added to the tissue inhibitor of metalloproteinase-1 (TIMP-1). Results The plasma concentration of ITIH3 in CRC patients (median: 4.370 μg/mL; range: 2.152–8.170 μg/mL) was significantly lower than that in healthy subjects (median: 4.715 μg/mL; range: 2.665–10.257 μg/mL; p < 0.001), while the ITIH4 plasma level in subjects with CRC (median: 0.211 μg/mL; range: 0.099–0.592 μg/mL) was markedly increased relative to that in the control group (median: 0.134 μg/mL; range: 0.094–0.460 μg/mL, p < 0.001). Consistently, IHC score assessment showed a dramatic reduction in ITIH3 expression and, conversely, upregulation of ITIH4 in colorectal carcinoma specimens relative to adjacent normal colorectal tissues (p < 0.001 in both cases). The area under the curve (AUC) of the ROC for ITIH4 (AUC = 0.801, 95% CI: 0.745–0.857) was higher than that for ITIH3 (AUC = 0.638, 95% CI: 0.571–0.704, both p values < 0.001). The AUC of the ROC for combined ITIH3 and ITIH4 was even higher than that for carcinoembryonic antigen. NRI results showed that combining ITIH3 and ITIH4 with TIMP-1 significantly improved diagnostic accuracy (NRI = 17.12%, p = 0.002) for CRC patients compared to TIMP-1 alone. Conclusions Circulating ITIH3 and ITIH4 levels are associated with carcinogenesis in CRC, supporting their potential diagnostic utility as surrogate biomarkers for colorectal cancer detection.

Prokineticin 2 expression as a novel prognostic biomarker for human colorectal cancer

Molecular tumor biomarkers hold considerable promise for accurately predicting colorectal cancer (CRC) recurrence and progression. Prokineticin 2 (PROK2) may be associated with angiogenesis and tumor formation in some malignant tumors. However, its prognostic value remains unknown. We focused on the association between PROK2 expression and clinical characteristics of CRC to assess value of PROK2 as a potential biomarker for stage I–III CRC patients prognosis.Between 1992 and 2006, 436 consecutive patients with stage I–III CRC treated with curative resection were included. PROK2 expression in primary tumors was investigated using immunohistochemistry. An animal model of liver metastasis was used to assess the role of PROK2.Positive PROK2 expression in primary tumors was found in 222 of 436 (50.9%) human CRC specimens and was significantly associated with lymphatic invasion, lymph node metastasis, clinical stage, and postoperative liver recurrence rate. Recurrence-free survival was significantly shorter in patients with positive PROK2 expression than in those with negative PROK2 expression. PROK2 expression was an independent unfavorable prognostic indicator for CRC [hazards ratio, 2.119; 95% confidence interval, 1.315–3.415; p = 0.002]. PROK2 overexpression promoted liver metastasis in vivo.We suggest that positive PROK2 expression is observed in CRC primary tissues; thus, PROK2 may be a useful predictor for liver recurrence and prognosis in CRC.

Circular RNA hsa_circ_0000567 can be used as a promising diagnostic biomarker for human colorectal cancer.

Recent studies have revealed that circular RNAs are involved in the biological process of some kinds of human cancers. However, little is known about their diagnostic values and functions in colorectal cancer (CRC). The expression levels of hsa_circ_0000567 in 102 paired CRC tissues and adjacent noncancerous tissues, 5 CRC cell lines, and a normal colorectal epithelial cell line were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The correlations between hsa_circ_0000567 expression levels and the clinicopathological factors of patients with CRC were analyzed. Furthermore, the loss-of-function assay was performed to investigate the functions of hsa_circ_0000567 in vitro. Finally, a receiver operating characteristic (ROC) curve was established to evaluate the diagnostic value of hsa_circ_0000567. Hsa_circ_0000567 expression was significantly downregulated in CRC tissues and CRC cell lines. In addition, the decreased hsa_circ_0000567 expression in CRC was negatively correlated with tumor size (P=.011), lymph metastasis (P=.003), distal metastasis (P<.0001), and tumor-node-metastasis (TNM) stage (P=.003) in CRC. Moreover, knockdown of hsa_circ_0000567 promoted CRC cells proliferation and migration in vitro. Importantly, the area under the ROC curve (AUC) was 0.8653, which indicates hsa_circ_0000567 can serve as a diagnostic biomarker. Hsa_circ_0000567 may be a novel suppressor and a potential diagnosis biomarker in CRC.

Two new molecular biomarkers in human colorectal cancer

Two new molecular biomarkers in human colorectal cancer

Elevated transgelin/TNS1 expression is a potential biomarker in human colorectal cancer.

Transgelin is an actin-binding protein that regulates cell motility and other important cellular functions. Previous studies have suggested that transgelin expression is associated with cancer development and progression, but its specific role in colorectal cancer (CRC) remains controversial. We analyzed expression of transgelin and its candidate downstream target, tensin 1 (TNS1), in CRC patients using the ONCOMINE, Protein Atlas, and OncoLnc databases. Transgelin and TNS1 mRNA and protein levels were higher in CRC patients and CRC cell lines than in normal tissues and cells. Survival analyses using the OncoLnc database revealed that elevated TAGLN/TNS1 levels were associated with a poor overall survival in CRC patients. Transgelin suppression using siRNA decreased TNS1 expression in CRC cells, demonstrating that transgelin induces the TNS1 expression. Importantly, suppression of transgelin or TNS1 using siRNA decreased proliferation and invasiveness of CRC cells. These results suggest that transgelin/TNS1 signaling promotes CRC cell proliferation and invasion, and that transgelin/TNS1 expression levels could potentially serve as a prognostic and therapeutic target in CRC patients.

Cancer-type OATP1B3 mRNA has the potential to become a detection and prognostic biomarker for human colorectal cancer.

We aimed to clarify diagnostic and prognostic biomarker potentials of cancer-type organic anion transporting polypeptide 1B3 (Ct-OATP1B3) mRNA in colorectal cancer (CRC) patients. Ct-OATP1B3 mRNA levels in 97 CRC and adjacent normal colon tissues were measured by real-time PCR. The receiver operating characteristic curve analysis and the Kaplan-Meier curve analysis were performed to characterize its biomarker potentials. Ct-OATP1B3 mRNA showed noticeable diagnostic power (the area under the receiver operating characteristic = 0.91) in the CRC patients. Additionally, the higher/lower mRNA expression was clearly associated with better/poorer overall survival in the CRC patients (p < 0.05). Ct-OATP1B3 mRNA has the potential to be a tissue-based biomarker for definitive diagnosis and prognostic stratification in CRC.

Effect of N-Wasp knockout on tumour burden and survival in murine models of intestinal tumorigenesis and its potential as a prognostic biomarker in human colorectal cancer

BackgroundAPC loss is a common initiating event in colorectal cancer but additional mutations are required for progression along the adenoma–carcinoma pathway. The Neural Wiskott–Aldrich syndrome protein (N-WASP) is crucial for invasion in a variety of cancers. Its role in colorectal cancer has not been investigated; however, it is implicated in Wnt signalling (the pathway affected when APC function is lost). The aim of this project was to investigate the role of N-WASP in intestinal tumorigenesis and its potential as a prognostic biomarker. MethodsThe effect of N-Wasp knockout (N-Waspfl/fl) on survival and tumour burden was investigated using two established murine models of intestinal tumorigenesis (Apcfl/+ and Apcfl/+ KrasG12D/+). Immunohistochemistry for N-WASP was performed on two human tissue microarrays—namely, colorectal cancers with linked clinicopathological data and long-term follow-up, and early cancers diagnosed via bowel screening. N-WASP expression was assessed by weighted histoscore, and correlation with survival was tested. FindingsN-Wasp knockout decreased survival in the Apcfl/+ model (median survival 143 days [IQR 127·3–167·0] vs 269 [228·8–304·5], p<0·0001) and developed more small intestinal tumours (mean 39·7 tumours [SD 14·24] vs 8 [4·34], p<0·0001). Interestingly, although mean tumour size was decreased in Apcfl/+ N-Waspfl/fl mice compared with Apcfl/+ mice (0·538 mm2 [SD 0·238] vs 1·547 [0·609], p=0·0317), there was no difference in mean size of the largest tumour. There was no effect of N-Wasp knockout on survival or small intestinal tumour burden in the Apcfl/+ KrasG12D/+ model. However, they developed fewer colonic tumours (mean 16·8 [SD 10·2] vs 35·4 [11·5], p=0·0018). In the human tissue microarray studies, there was no difference in overall or cancer-specific survival between tumours with high and low N-WASP expression. InterpretationWe found that loss of N-Wasp promotes early tumorigenesis in Apc-deficient intestinal epithelium in mice. N-WASP stabilises epithelial cell–cell junctions and might be a regulator of Wnt signalling. Further research is required to ascertain whether either of these roles explains the effects seen here and whether it promotes invasion and metastasis in more advanced intestinal cancers, as seen in other tissues. FundingFunded by a Medical Research Council grant via the Scottish Clinical Pharmacology and Pathology Programme (SCP3).

Circulating microRNA-1290 as a novel diagnostic and prognostic biomarker in human colorectal cancer

Circulating microRNAs (miRNAs) are attracting major interest as potential non-invasive biomarkers for colorectal cancer (CRC). This study aimed to identify a novel serum miRNA biomarker for the early detection and/or evaluating prognosis of CRC patients. Comprehensive miRNA array analysis was carried out using serum samples from patients with colorectal neoplasia and healthy controls. Next, to verify whether the candidate miRNA possessed a secretory potential, we screened miRNA expression levels in culture medium from 2 CRC cell lines, followed by serum analysis from 12 stage IV CRC, 12 adenoma, and 12 control subjects. Thereafter, we validated expression of candidate miRNAs in 179 primary CRC tissues, as well as serum samples from an independent cohort of 211 CRCs, 56 adenomas, and 57 control subjects. Through microarray analysis, we identified significantly higher levels of miRNA-1290 (miR-1290) in serum from patients with colorectal adenomas and cancers. We verified miR-1290 overexpression in serum of CRC patients in a training cohort. In the validation cohort, serum miR-1290 levels were significantly up-regulated in patients with colorectal adenomas (P < 0.0001) and cancers (P < 0.0001). Serum miR-1290 levels could robustly distinguish adenoma [area under the curve (AUC) = 0.718] and CRC patients (AUC = 0.830) from normal subjects. High miR-1290 expression in serum and tissue was significantly associated with tumor aggressiveness and poor prognosis. Moreover, serum miR-1290 levels were an independent prognostic factor [hazard ratio (HR) = 4.51; 95% confidence interval (CI) = 1.23-23.69; P = 0.0096] and an independent predictor for tumor recurrence (hazard ratio = 3.92; 95% confidence interval = 1.11-25.14; P = 0.032) in CRC. Serum miR-1290 is a novel biomarker for early detection, recurrence, and prognosis in CRC.

Abstract 968: Circulating microRNA-1290 as a novel diagnostic and prognostic biomarker in human colorectal cancer

Abstract Background &amp; Aims: MicroRNAs (miRNAs) play a crucial role in diverse cellular biological processes such as differentiation, proliferation, migration, invasion and survival. MiRNA expression patterns are found to be frequently dysregulated in human tumors, which is currently being exploited both from a basic science perspective and for its clinical usefulness as disease biomarkers. Circulating miRNAs are attracting major interest as potential noninvasive biomarkers for colorectal cancer (CRC). This study aimed to identify a novel serum miRNA biomarker for the early detection and/or evaluating prognosis of CRC patients. Methods: Comprehensive miRNA array analysis was performed using serum samples from patients with colorectal neoplasia (CRC: n = 3, adenoma: n = 3) and healthy controls (n = 3). Next, to verify whether the candidate miRNA possessed a secretory potential, we screened miRNA expression levels in culture medium from 2 CRC cell lines, followed by serum analysis from 12 stage IV CRC, 12 adenoma and 12 control subjects. Thereafter, we validated expression of candidate miRNAs in 179 primary CRC tissues, as well as serum samples from an independent cohort of 211 CRCs, 56 adenomas, and 57 control subjects. Results: Through microarray analysis, we identified significantly higher levels of miRNA-1290 (miR-1290) in serum from patients with colorectal adenomas and cancers. We verified miR-1290 overexpression in serum of CRC patients in a training cohort. In the validation cohort, serum miR-1290 levels were significantly upregulated in patients with colorectal adenomas (P &amp;lt; 0.0001) and cancers (P &amp;lt; 0.0001). Serum miR-1290 levels could robustly distinguish adenoma (area under the curve [AUC] = 0.718) and CRC patients (AUC = 0.830) from normal subjects. Serum miR-1290 levels significantly diminished after surgical resection of the primary tumor in the same patients’ serum specimens (P &amp;lt; 0.0001). In addition, we observed a statistically significant positive correlation of miR-1290 expression levels between primary CRC tissues and matched serum samples (ρ = 0.482; P &amp;lt; 0.0001). High miR-1290 expression in serum and tissue was significantly associated with tumor aggressiveness and poor prognosis. Moreover, serum miR-1290 levels were an independent prognostic factor in CRC patients (hazard ratio = 4.51; 95% confidence interval = 1.23-23.69; P = 0.0096). Conclusions: Serum miR-1290, which might be secreted from primary CRC, is a novel diagnostic and prognostic biomarker in CRC. Citation Format: Yuji Toiyama, Hiroki Imaoka, Hiroyuki Fujikawa, Junichiro Hiro, Susumu Saigusa, Koji Tanaka, Yasuhiro Inoue, Yasuhiko Mohri, Takao Mori, Toshio Kato, Ajay Goel, Masato Kusunoki. Circulating microRNA-1290 as a novel diagnostic and prognostic biomarker in human colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 968.

Long noncoding RNA GAS5 affects cell proliferation and predicts a poor prognosis in patients with colorectal cancer.

Colorectal cancer (CRC) is the third most common type of cancer worldwide. Recent studies have shown that lncRNAs play important roles in carcinogenesis. The aim of this study was to explore the role of lncRNA GAS5 in CRC. Real-time PCR was performed to investigate the expression of GAS5 in tumor tissues and corresponding non-tumor colorectal tissues from 66 patients with CRC. The lower expression of GAS5 was significantly correlated with large tumor size, low histological grade and advanced TNM stage. Multivariate analyses revealed that GAS5 expression served as an independent predictor for overall survival (P = 0.034). Further experiments revealed that overexpressed GAS5 significantly repressed the proliferation both in vitro and in vivo. In conclusion, our results suggest that GAS5, as a growth regulator, may serve as a candidate prognostic biomarker in human colorectal cancer.

Identification of SOCS2 and SOCS6 as biomarkers in human colorectal cancer.

Background:Over the past years, some members of the family of suppressor of cytokine signalling (SOCS) proteins have emerged as potential tumour suppressors. This study aimed at investigating the clinical significance of SOCS proteins in colorectal carcinoma (CRC).Methods:We integrated publicly available microarray expression data on CRC in humans, analysed the expression pattern of SOCSs and assessed the predictive power of SOCS2 and SOCS6 for diagnostic purposes by generating receiver operating characteristic curves. Using laser microdissected patient material we assessed SOCS expression on RNA and protein levels as well as their methylation status in an independent CRC patient cohort. Finally, we investigated the prognostic value of SOCS2 and SOCS6.Results:The meta-analysis as well as the independent patient cohort analysis reveal a stage-independent downregulation of SOCS2 and SOCS6 and identify both molecules as diagnostic biomarkers for CRC. We demonstrate a different methylation pattern within the SOCS2 promoter between tumour tissue and normal control tissue in 25% of CRC patients. Furthermore, early CRC stage patients with low expression of SOCS2 display significantly shorter disease-free survival.Conclusions:Our data offers evidence that SOCS2 and SOCS6 levels are reduced in CRC and may serve as diagnostic biomarkers for CRC patients.