Identification of a lncRNA prognostic signature-related to stem cell index and its significance in colorectal cancer.

Background: The relationship between long noncoding RNAs (lncRNAs) and the mRNA stemness index (mRNAsi) in colorectal cancer (CRC) is still unclear. Materials & methods: The mRNAsi, mRNAsi-related lncRNAs and their clinical significance were analyzed by bioinformatic approaches in The Cancer Genome Atlas (TCGA)-COREAD dataset. Results: mRNAsi was negatively related to pathological features but positively related to overall survival and recurrence-free survival in CRC. A five mRNAsi-related lncRNAs prognostic signature was further developed and showed independent prognostic factors related to overall survival in CRC patients, due to the five mRNAsi-related lncRNAs involved in several pathways of the cancer stem cells and malignant cancer cell phenotypes. Conclusion: The present study highlights the potential roles of mRNAsi-related lncRNAs as alternative prognostic markers.

Lay abstract Previous evidence has indicated that the mRNA stem index (mRNAsi) is representative of the stemness of cancer stem cells (CSCs), whereas long noncoding RNAs (lncRNAs) may be crucial regulators in CSC phenotype. Nevertheless, the relationship between lncRNAs and mRNAsi in CRC is still unclear. Our results show that the mRNAsi was negatively related to pathological features and positively related to prognosis in CRC. Five mRNAsi-related lncRNAs were further identified and developed as a prognostic signature that could independently predict survival in CRC patients due to the five mRNAsi-related lncRNAs being involved in several pathways of CSCs and malignant cancer cell phenotypes, indicating the potential roles of mRNAsi-related lncRNAs as alternative prognostic markers.

Expression profile, molecular functions, and prognostic significance of miRNAs in primary colorectal cancer stem cells.

MicroRNAs (miRNAs) are known to drive the pathogenesis of colorectal cancer (CRC) via the regulation of cancer stem cells (CSCs). We studied the miRNA expression profile of primary CSCs isolated from patients with CRC (pCRCSCs). Compared to pCRCSC-derived differentiated cells, 98 differentially expressed miRNAs were identified in pCRCSCs. Target genes encoding pCRCSC-related miRNAs were identified using a combination of miRNA target databases and miRNA-mRNA regulatory networks from the same patient. The pCRCSC-related miRNA target genes were associated with pathways contributing to malignant phenotypes, including I-kappa B kinase/NF-kappa B signaling, signal transduction by p53 class mediator, Ras signaling, and cGMP-PKG signaling. The pCRCSC-related miRNA expression signature was independently associated with poor overall survival in both the training and validation cohorts. We have thus identified several pCRCSC-related miRNAs with oncogenic potential that could serve as prognostic biomarkers for CRC.

High ANKZF1 expression is associated with poor overall survival and recurrence-free survival in colon cancer.

Aim: To investigate the association and prognostic value of ANKZF1 gene for survival in colorectal cancer, the mechanism of ANKZF1 level alteration and correlated signaling pathways ANKZF1 is involved. Patients & methods: The Cancer Genome Atlas COREAD dataset was analyzed by bioinformatical investigation. Results: High ANKZF1 expression is associated with poor overall survival (hazard ratio [HR]: 2.094; 95% CI: 1.188-3.689; p = 0.011) and recurrence-free survival (HR: 1.762; 95% CI: 1.021-3.042; p = 0.042) in colon cancer. Bioinformatical analysis showed ANKZF1 was upregulated by amplification and exon expression. ANKZF1 was associated with angiogenesis and cancer signaling pathways. Conclusion: High ANKZF1 is an independent factor of poor survival (overall survival and recurrence-free survival) in colon cancer by taking part in angiogenesis and some cancer signaling pathways.

Prognostic Heterogeneity of MRE11 Based on the Location of Primary Colorectal Cancer Is Caused by Activation of Different Immune Signals.

Background: MRE11 plays an important role in DNA damage response for the maintenance of genome stability, and is becoming a prognostic marker for cancers, including colorectal cancer (CRC). However, the correlations of MRE11 to prognosis and tumor-infiltrating inflammatory cells (TIICs) in different locations of CRC remains unclear. Methods: Among Swedish and TCGA-COREAD patients, we investigated the association of MRE11 expression, tumor-infiltrating inflammatory cells (TIICs) and microsatellite status with survival in right-sided colon cancer (RSCC) and left-sided colon and rectal cancer (LSCRC). The signaling of MRE11-related was further analyzed using weighted gene co-expression network analysis and ClueGO. Results: High MRE11 expression alone or combination of high MRE11 expression with high TIICs was related to favorable prognosis in LSCRC. Moreover, high MRE11 expression was associated with favorable prognosis in LSCRC with microsatellite stability. The relationships above were adjusted for tumor stage, differentiation, and/or TIICs. However, no such evidence was observed in RSCC. Several signaling pathways involving MRE11 were found to be associated with cell cycle and DNA repair in RSCC and LSCRC, whereas, the activation of the immune response and necrotic cell death were specifically correlated with LSCRC. Conclusions: High MRE11 expression is an independent prognostic marker in LSCRC and enhanced prognostic potency of combining high MRE11 with high TIICs in LSCRC, mainly due to differential immune signaling activated by MRE11 in RSCC and LSCRC, respectively.

Forced co-expression of IL-21 and IL-7 in whole-cell cancer vaccines promotes antitumor immunity.

Genetic modification of whole-cell cancer vaccines to augment their efficacies has a history of over two and a half decades. Various genes and gene combinations, targeting different aspects of immune responses have been tested in pursuit of potent adjuvant effects. Here we show that co-expression of two cytokine members of the common cytokine receptor γ-chain family, IL-21 and IL-7, in whole-cell cancer vaccines boosts antitumor immunity in a CD4(+) and CD8(+) T cell-dependent fashion. It also generates effective immune memory. The vaccine-elicited short-term effects positively correlated with enhanced infiltration of CD4(+) and CD8(+) effector T cells, and the long-term effects positively correlated with enhanced infiltration of effector memory T cells, especially CD8(+) effector memory T cells. Preliminary data suggested that the vaccine exhibited good safety profile in murine models. Taken together, the combination of IL-21 and IL-7 possesses potent adjuvant efficacy in whole-cell vaccines. This finding warrants future development of IL-21 and IL-7 co-expressing whole-cell cancer vaccines and their relevant combinatorial regimens.

Severe Hypoglycemia Caused by Recurrent Sarcomatoid Carcinoma in the Pelvic Cavity: A Case Report.

Nonislet cell tumor hypoglycemia (NICTH) is a paraneoplastic syndrome characterized by persistent, severe hypoglycemia in different tumor types of mesochymal or epithelial origin; however, NICTH is infrequently induced by sarcomatoid carcinoma (SC). Despite some sarcomatoid and epithelioid characteristics in few cases of malignancies from epithelium, NICTH induced by recurrent SC in pelvic cavity in this report is extremely rare.We report a case in which NICTH caused by recurrence and pulmonary metastases from SC in the pelvic cavity, and the computed tomography scan revealed multiple pelvic masses and multiple large masses in the pulmonary fields. During the treatment of intestinal obstruction, the patient presented paroxysmal loss of consciousness and sweating. Her glucose even reached 1.22 mmol/L while the serum glycosylated hemoglobin was normal and previous history of diabetes or use of oral hypoglycemic agents and insulin denied.The laboratory examination showed that the low level of insulin, C-peptide, and growth hormone levels in the course of hypoglycemic episodes suggesting to the diagnosis of hypoglycemia induced by nonislet cell tumor, and the decreased levels of insulin-like growth factor (IGF)-I and IGFBP3 and the high expression of big IGF-II in the serum further confirmed the diagnosis of NICTH. Because of the widely pelvic recurrence and pulmonary metastases were unresected, the patient was discharged from the hospital after 2 weeks treatment with dexamethasone and glucose and unfortunately died 1 week later.NICTH caused by SC in the pelvic cavity is extremely rare case in clinical. The aim of this report was to present the importance to examine big IGF-II expression in patient's serum in order to reach the diagnosis of NICTH in cases of intractable cancer-associated hypoglycemia.

Significance of HPV infection and genic mutation of APC and K-ras in patients with rectal cancer.

BACKGROUND: Significance of HPV infection and genic mutation of APC and K-ras in rectal cancer has been investigated but not clarified. The objective of our study was to investigate these parameters in patients with rectal cancer to analyze correlations with biological behaviour, to determine relationships among the three, and also to demonstrate survival prognosis effects. METHODS: From December 2007 to September 2008, 75 rectal cancer cases confirmed by histopathology in the Tumor Hospital of Xinjiang Medical University were enrolled. The control group consisted of normal rectal mucous membrane taken simultaneously, a least 10 cm distant from the carcinoma fringe. HPV DNA, the MCR of APC and exon-1 of K-ras were detected by PCR and PCR-SSCP. All results were analyzed in relation to clinical pathological material, using chi-square and correlation analysis via SPSS.13 and Fisher's Exact Probability via STATA. 9.0. All 75 patients were followed up for survival analysis using Kaplan-Meier and Log-rank tests. RESULTS: 55 out of 75 cases demonstrated gene HPV L1 while it was not detected in normal rectal mucosa tissue. HPV infection was correlated with age and lymphatic metastasis (P<0.05) but not other characteristics, such as ethnicity, tumor size, histological type, tumor type, Duke's stage and infiltration depth. Some 43 cases exhibited APC genic mutation (57.3%) and 34 K-ras genic mutation (45.3%). APC genic mutation was correlated with gender( P<0.05), but not age, histological type, infiltration depth, lymphatic metastasis and Duke's stage. In 55 cases of rectal cancer with HPV infection, there were 31 cases with genic mutation of APC (56.4%) and 24 with genic mutation of K-ras (43.6%). For the 20 cases of rectal cancer with non-HPV infection, the figures were 12 cases (60%) and 10 (50.0%), respectively, with no significant relation. Survival analysis showed no statistical significance for K-ras genic mutation, APC genic mutation or HPV infection (P>0.05). However, the survival time of the patients with HPV infection was a little shorter than in cases without HPV infection. CONCLUSIONS: Our results suggest that HPV infection might be an important factor to bring about malignant phenotype of rectal cancer and influence prognosis. Genic mutation of APC and K-ras might be common early molecular events of rectal cancer, but without prognostic effects on medium-term or early stage patients with rectal cancer.

Prognostic significance of relevant markers of cancer stem cells in colorectal cancer - a meta analysis.

BACKGROUND/AIMS: To evaluate the correlation between the expression of stem cell makers and prognosis in colorectal cancer. METHODOLOGY: Eligible studies evaluating the correlation between stem cell makers and prognosis were selected based on the references in PubMed, Embase and Cochrane libraries. Outcome measures included overall survival, relevant pathological parameters. Meta-analyses were performed by RevMan 5.0. RESULTS: Seventeen eligible articles involving 3098 patients were included. Meta-analysis showed CD44 expression is not significant difference of 5-year overall survival rate (OR=0.69, p=0.22) and relevant clinical parameters, such as histological grade (OR=1.98, p=0.06), dukes grade (OR=0.77, p=0.43) and metastasis (OR=1.03, p=0.89). Likewise, there is no correlation between CD44v6 and dukes stage (OR=0.56, p=0.23), metastasis (OR= 2.81, p=0.33), except for histological grade (OR=0.48, p=0.02). However, CD44v6 positive cells (OR=0.36, p=0.02) were significantly associated with poor overall survival. CONCLUSIONS: Based on current retrospective evidence, a stem cell maker, CD44 cannot become a prognostic marker in colorectal cancer. In contrast, CD44v6, an isoform of CD44 plays a significant role to predict clinic outcome.