Regulatory RNAs, microRNA, long-non coding RNA and circular RNA roles in colorectal cancer stem cells.

The properties of cancer stem cells (CSCs), such as self-renewal, drug resistance, and metastasis, have been indicated to be responsible for the poor prognosis of patients with colon cancers. The epigenetic regulatory network plays a crucial role in CSC properties. Regulatory non-coding RNA (ncRNA), including microRNAs, long noncoding RNAs, and circular RNAs, have an important influence on cell physiopathology. They modulate cells by regulating gene expression in different ways. This review discusses the basic characteristics and the physiological functions of colorectal cancer (CRC) stem cells. Elucidation of these ncRNAs will help us understand the pathological mechanism of CRC progression, and they could become a new target for cancer treatment.

Cytomegalovirus proctitis in non-human immunodeficiency virus infected patients: A case report and literature review.

Cytomegalovirus (CMV) infection is associated with significant morbidity and mortality in both immunocompetent and immunocompromised patients. CMV is a ubiquitous Herpesviridae virus with a wide spectrum of pathologies in humans. Immunocompetent patients generally develop a benign, self-limited mononucleosis-like syndrome, whereas gastrointestinal tissue-invasive disease is more frequently seen in immunocompromised. The clinical manifestations of CMV colitis or proctitis are demarcated by bloody diarrhea, ulcerations, ulcero-infiltrative changes, and pseudomembranous formation on colonoscopy. Gastrointestinal CMV infections complicated with deep rectal ulcer and fistula formation are rare in patients with systemic lupus erythematosus. Ganciclovir is also the gold standard therapy for CMV colitis or proctitis.

Chitosan 3D cell culture system promotes naïve-like features of human induced pluripotent stem cells: A novel tool to sustain pluripotency and facilitate differentiation.

A simplified and cost-effective culture system for maintaining the pluripotency of human induced pluripotent stem cells (hiPSCs) is crucial for stem cell applications. Although recombinant protein-based feeder-free hiPSC culture systems have been developed, their manufacturing processes are expensive and complicated, which hinders hiPSC technology progress. Chitosan, a versatile biocompatible polysaccharide, has been reported as a biomaterial for three-dimensional (3D) cell culture system that promotes the physiological activities of mesenchymal stem cells and cancer cells. In the current study, we demonstrated that chitosan membranes sustained proliferation and pluripotency of hiPSCs in long-term culture (up to 365 days). Moreover, using vitronectin as the comparison group, the pluripotency of hiPSCs grown on the membranes was altered into a naïve-like state, which, for pluripotent stem cells, is an earlier developmental stage with higher stemness. On the chitosan membranes, hiPSCs self-assembled into 3D spheroids with an average diameter of ~100 µm. These hiPSC spheroids could be directly differentiated into lineage-specific cells from the three germ layers with 3D structures. Collectively, chitosan membranes not only promoted the naïve pluripotent features of hiPSCs but also provided a novel 3D differentiation platform. This convenient biomaterial-based culture system may enable the effective expansion and accessibility of hiPSCs for regenerative medicine, disease modeling, and drug screening.

SIRT1-Mediated Expression of CD24 and Epigenetic Suppression of Novel Tumor Suppressor miR-1185-1 Increases Colorectal Cancer Stemness.

NAD-dependent deacetylase sirtuin-1 (SIRT1) is a class III histone deacetylase that positively regulates cancer-related pathways such as proliferation and stress resistance. SIRT1 has been shown to promote progression of colorectal cancer and is associated with cancer stemness, yet the precise mechanism between colorectal cancer stemness and SIRT1 remains to be further clarified. Here we report that SIRT1 signaling regulates colorectal cancer stemness by enhancing expression of CD24, a colorectal cancer stemness promoter. A novel miRNA, miR-1185-1, suppressed the expression of CD24 by targeting its 3'UTR (untranslated region) and could be inhibited by SIRT1 via histone deacetylation. Targeting SIRT1 by RNAi led to elevated H3 lysine 9 acetylation on the promoter region of miR-1185-1, which increased expression of miR-1185-1 and further repressed CD24 translation and colorectal cancer stemness. In a mouse xenograft model, overexpression of miR-1185-1 in colorectal cancer cells substantially reduced tumor growth. In addition, expression of miR-1185-1 was downregulated in human colorectal cancer tissues, whereas expression of CD24 was increased. In conclusion, this study not only demonstrates the essential roles of a SIRT1-miR-1185-1-CD24 axis in both colorectal cancer stemness properties and tumorigenesis but provides a potential therapeutic target for colorectal cancer treatment. SIGNIFICANCE: A novel tumor suppressor miR-1185-1 is involved in molecular regulation of CD24- and SIRT1-related cancer stemness networks, marking it a potential therapeutic target in colorectal cancer. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/23/5257/F1.large.jpg.

Patient-derived induced pluripotent stem cells for models of cancer and cancer stem cell research.

Induced pluripotent stem cells (iPSCs) are embryonic stem cell-like cells reprogrammed from somatic cells by four transcription factors, OCT4, SOX2, KLF4 and c-MYC. iPSCs derived from cancer cells (cancer-iPSCs) could be a novel strategy for studying cancer. During cancer cell reprogramming, the epigenetic status of the cancer cell may be altered, such that it acquires stemness and pluripotency. The cellular behavior of the reprogrammed cells exhibits dynamic changes during the different stages of reprogramming. The cells may acquire the properties of cancer stem cells (CSCs) during the process of reprogramming, and lose their carcinogenic properties during reprogramming into a cancer-iPSCs. Differentiation of cancer-iPSCs by teratoma formation or organoid culturing could mimic the process of tumorigenesis. Some of the molecular mechanisms associated with cancer progression could be elucidated using the cancer-iPSC model. Furthermore, cancer-iPSCs could be expanded in culture system or bioreactors, and serve as cell sources for research, and as personal disease models for therapy and drug screening. This article introduces cancer studies that used the cell reprogramming strategy.

Highly Efficient Intracellular Protein Delivery by Cationic Polyethyleneimine-Modified Gelatin Nanoparticles.

Intracellular protein delivery may provide a safe and non-genome integrated strategy for targeting abnormal or specific cells for applications in cell reprogramming therapy. Thus, highly efficient intracellular functional protein delivery would be beneficial for protein drug discovery. In this study, we generated a cationic polyethyleneimine (PEI)-modified gelatin nanoparticle and evaluated its intracellular protein delivery ability in vitro and in vivo. The experimental results showed that the PEI-modified gelatin nanoparticle had a zeta potential of approximately +60 mV and the particle size was approximately 135 nm. The particle was stable at different biological pH values and temperatures and high protein loading efficiency was observed. The fluorescent image results revealed that large numbers of particles were taken up into the mammalian cells and escaped from the endosomes into the cytoplasm. In a mouse C26 cell-xenograft cancer model, particles accumulated in cancer cells. In conclusion, the PEI-modified gelatin particle may provide a biodegradable and highly efficient protein delivery system for use in regenerative medicine and cancer therapy.

Glypican-3 induces oncogenicity by preventing IGF-1R degradation, a process that can be blocked by Grb10.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is a major cause of cancer-related death worldwide. Previously, we demonstrated that glypican-3 (GPC3) is highly expressed in HCC, and that GPC3 induces oncogenicity and promotes the growth of cancer cells through IGF-1 receptor (IGF-1R). In the present study, we investigated the mechanisms of GPC3-mediated enhancement of IGF-1R signaling. We demonstrated that GPC3 decreased IGF-1-induced IGF-1R ubiquitination and degradation and increased c-Myc protein levels. GPC3 bound to Grb10, a mediator of ligand-induced receptor ubiquitination, and the overexpression of Grb10 blocked GPC3-enhanced IGF-1-induced ERK phosphorylation. GPC3 promoted the growth of NIH3T3 and PLC-PRF-5 cells in serum-free medium but did not promote the growth of IGF-1R negative R- cells. Grb10 overexpression decreased GPC3-promoted cell growth. Therefore, the present study elucidates the mechanisms of GPC3-induced oncogenicity, which may highlight new strategies for the treatment of HCC.

Chitosan promotes cancer progression and stem cell properties in association with Wnt signaling in colon and hepatocellular carcinoma cells.

Cancer stem cells (CSCs), a small population of cancer cells, have been considered to be the origin of cancer initiation, recurrence, and metastasis. Tumor microenvironment provides crucial signals for CSCs to maintain stem cell properties and promotes tumorigenesis. Therefore, establishment of an appropriate cell culture system to mimic the microenvironment for CSC studies is an important issue. In this study, we grew colon and hepatocellular carcinoma (HCC) cells on chitosan membranes and evaluated the tumor progression and the CSC properties. Experimental results showed that culturing cancer cells on chitosan increased cell motility, drug resistance, quiescent population, self-renewal capacity, and the expression levels of stemness and CSC marker genes, such as OCT4, NANOG, CD133, CD44, and EpCAM. Furthermore, we demonstrated that chitosan might activate canonical Wnt/ß-catenin-CD44 axis signaling in CD44positive colon cancer cells and noncanonical Wnt-STAT3 signaling in CD44negative HCC cells. In conclusion, chitosan as culture substrates activated the essential signaling of CSCs and promoted CSC properties. The chitosan culture system provides a convenient platform for the research of CSC biology and screening of anticancer drugs.

Y-box binding protein-1 promotes hepatocellular carcinoma-initiating cell progression and tumorigenesis via Wnt/ß-catenin pathway.

Y-box binding protein-1 (YB-1) is a pleiotropic molecule that binds DNA to regulate genes on a transcriptional level in the nucleus and binds RNA to modulate gene translation in the cytoplasm. In our previous studies, YB-1 was also characterized as a fetal hepatic protein that regulates the maturation of hepatocytes and is upregulated during liver regeneration. Moreover, YB-1 has been shown to be expressed in human hepatocellular carcinoma (HCC). However, the role of YB-1 in HCC remains unclear. Here, we aimed to characterize the role of YB-1 in HCC. Based on the results of loss-of-function in HCC and gain-of-function in mice liver using hydrodynamic gene delivery, YB-1 promoted hepatic cells proliferation in vitro and in vivo. YB-1 was also involved in HCC cell proliferation, migration, and drug-resistance. The results of extreme limiting dilution sphere forming analysis and cancer initiating cell marker analysis were also shown that YB-1 maintained HCC initiating cells population. YB-1 also induced the epithelial-mesenchymal transition and stemness-related gene expression. Knockdown of YB-1 suppressed the expression of Wnt ligands and ß-catenin, impaired Wnt/ß-catenin signaling pathway and reduced the numbers of HCC initiating cells. Moreover, YB-1 displayed nuclear localization particularly in the HCC initiating cells, the EpCAM+ cells or sphere cells. Our findings suggested that YB-1 was a key factor in HCC tumorigenesis and maintained the HCC initiating cell population.

Robot-assisted intersphincteric resection for rectal submucosal tumour.

BACKGROUND: Rectal submucosal tumours are rare. The purpose of this study was to evaluate the safety and feasibility of robot-assisted rectal surgery. METHODS: Patients who received robot-assisted intersphincteric resection (ISR) were included in the present study. Clinical outcomes, operating time, length of hospital stay and pathological status were analysed. RESULTS: There were three patients with gastrointestinal tumours and three patients diagnosed with neuroendocrine tumours. The mean operating time was 369.2 min and the estimated blood loss was 66.7 ml. There were neither intraoperative complications nor conversions. On pathological examination, the mean number of lymph nodes harvested was 10.3 (range 3-16), the mean distal resection margin was 1.1 (range 0.1-3) cm and all six patients had the circumferential resection margins clear. CONCLUSIONS: Our data show that robotic surgery is feasible and safe, with no morbidity or mortality, and that ISR provides bowel continuity and eliminates the need for colostomy. Copyright © 2015 John Wiley & Sons, Ltd.