Gastrointestinal (GI) cancer, including gastric and colorectal cancer, is a major cause of death worldwide. A substantial proportion of patients with GI cancer have a familial history, and several causative genes have been identified. Gene carriers with these hereditary GI syndromes often harbor several kinds of cancer at an early age, and genetic testing and specific surveillance may save their lives through early detection. Gastroenterologists and GI surgeons should be familiar with these syndromes, even though they are not always associated with a high penetrance of GI cancer. In this review, we provide an overview and discuss the diagnosis, genetic testing, and management of four major hereditary GI cancers: familial adenomatous polyposis, Lynch syndrome, hereditary diffuse gastric cancer, and Li-Fraumeni syndrome.

In recent years, the tissue inhibitor of metalloproteinase-3 (TIMP3) plays a pivotal role in tumorigenesis, while the role of TIMP3 in adrenocorticotrophic hormone (ACTH)-secreting pituitary adenomas remains unclear. In this study, 86 sporadic pituitary tumor specimens, including ACTH (40), GH (18), PRL-secreting (8), and non-functioining (20) and non-tumorous pituitary samples (n = 10) were available, and then, the mRNA and protein expression of TIMP3 was quantified by quantitative reverse transcriptase polymerase chain reaction (RT-PCR), western blotting, and immunohistochemistry, respectively. Our findings showed that TIMP3 expression was significantly correlated with Ki-67 expression and the invasiveness of pituitary adenomas. TIMP3 mRNA and protein expression were reduced in ACTH-secreting pituitary adenomas and the other three types of pituitary adenomas compared to adjacent non-tumorous pituitary tissues (all p < .01). On the other hand, the expression of TIMP3 was negatively correlated with tumor size and Ki-67 in ACTH-secreting pituitary adenomas. TIMP3 mRNA expression was significantly lower in invasive pituitary adenomas than that in noninvasive ones (1.92-fold, p < .05). TIMP3 protein levels were also significantly lower in the majority of invasive adenomas (1.41-fold, p < .05) Furthermore, TIMP3 mRNA and protein expression were significantly lower in pituitary giant adenomas than those in microadenomas (2.58-fold, p < .05). In conclusion, the expression of TIMP3 is low in pituitary adenomas including ACTH-secreting pituitary adenomas and negatively associated with tumor aggressiveness. TIMPs may play a potential role in the progression of ACTH-secreting pituitary adenomas and be useful as a biomarker of invasiveness.

Osteosarcoma is the most common type of primary malignant tumor of the bone. However, mechanisms underlying osteosarcoma cell proliferation are poorly understood. The present study shows that RBEL1, a newly identified Rab-like GTPase, may be a key regulator of osteosarcoma cell proliferation. Knockdown of RBEL1 in osteosarcoma cells resulted in impaired colony formation and cell proliferation. Cell cycle analysis suggested that RBEL1 depletion induced G1-S arrest in osteosarcoma cells. Furthermore, it was demonstrated that retinoblastoma 1 (Rb) was upregulated and activated following RBEL1 knockdown. In addition, Rb inhibitory downstream targets, such as cyclin A2, cyclin D1, c-Myc and cyclin-dependent kinase 2, were downregulated. Rb knockdown reversed RBEL1 depletion-induced tumor suppressive effects. In conclusion, the present results suggest that RBEL1 modulates cell proliferation and G1‑S transition by inhibiting Rb in osteosarcoma. These results suggest a potential therapeutic target in osteosarcoma.

Epigenetic regulation plays a significant role in gliomas. However, how methylation and long non-coding RNA (lncRNA) cooperates to regulate gliomas progression is largely unknown. In this investigation we showed that the downregulation of MEG3 expression due to hypermethylation of MEG3 was observed in gliomas tissues. Treatment of glioma cells with the DNA methylation inhibitor 5-Aza-2'-deoxycytidine (5-AzadC) decreased aberrant hypermethylation of the MEG3 promoter and prevented the loss of MEG3 expression. In addition, DNMT1 was involved in MEG3 promoter methylation, and was inversely correlated with MEG3 expression in gliomas. The inhibition of DNMT1 repressed the proliferation, clone formation, and induced apoptosis in glioma cells. Importantly, the inhibition of DNMT1 contributed to the activation of p53 pathways in gliomas cells. These results suggest that DNMT1-mediated MEG3 hypermethylation caused the loss of MEG3 expression, followed by the inhibition of the p53 pathways in gliomas.

For the clinician, despite its rarity, adrenocortical cancer is a heterogeneous tumor both in term of steroid excess and tumor evolution. For patient management, it is crucial to have an accurate vision of this heterogeneity, in order to use a correct tumor classification. Pathology is the best way to classify operated adrenocortical tumors: to recognize their adrenocortical nature and to differentiate benign from malignant tumors. Among malignant tumors pathology also aims at prognosis assessment. Although progress has being made for prognosis assessment, there is still a need for improvement. Recent studies have established the value of Ki67 for adrenocortical cancer (ACC) prognostication, aiming also at standardization to reduce variability. The use of genomics to study adrenocortical tumors gives a very new insight in their pathogenesis and molecular classification. Genomics studies of ACC give now a clear description of the mRNA (transcriptome) and miRNA expression profile, as well as chromosomal and methylation alterations. Exome sequencing also established firmly the list of the main ACC driver genes. Interestingly, genomics study of ACC also revealed subtypes of malignant tumors with different pattern of molecular alterations, associated with different outcome. This leads to a new vision of adrenocortical tumors classification based on molecular analysis. Interestingly, these molecular classifications meet also the results of pathological analysis. This opens new perspectives on the development and use of various molecular tools to classify, along with pathological analysis, ACC, and guides patient management at the area of precision medicine.

Wild-type TP53 exons 5-8 contain CpG dinucleotides that are prone to methylation-dependent mutation during carcinogenesis, but the regulatory effects of methylation affecting these CpG sites are unclear. To clarify this, we first assessed site-specific TP53 CpG methylation in normal and transformed cells. Both DNA damage and cell ageing were associated with site-specific CpG demethylation in exon 5 accompanied by induction of a truncated TP53 isoform regulated by an adjacent intronic promoter (P2). We then synthesized novel synonymous TP53 alleles with divergent CpG content but stable encodement of the wild-type polypeptide. Expression of CpG-enriched TP53 constructs selectively reduced production of the full-length transcript (P1), consistent with a causal relationship between intragenic demethylation and transcription. 450K methylation comparison of normal (TP53-wildtype) and cancerous (TP53-mutant) human cells and tissues revealed focal cancer-associated declines in CpG methylation near the P1 transcription start site, accompanied by rises near the alternate exon 5 start site. These data confirm that site-specific changes of intragenic TP53 CpG methylation are extrinsically inducible, and suggest that human cancer progression is mediated in part by dysregulation of damage-inducible intragenic CpG demethylation that alters TP53 P1/P2 isoform expression. © 2015 The Authors. Molecular Carcinogenesis Published by Wiley Periodicals, Inc.

Colorectal cancer is a common malignant disease, the incidence of which is increasing worldwide, therefore, identifying novel prognostic factors to improve adjuvant therapeutic strategies or postoperative monitoring is required. Angiogenesis, which is assessed by microvessel density (MVD), is significant in tumor growth and metastasis. However, the association between angiogenesis and clinical outcome remains controversial. In the present study, 84 surgically resected cases of colorectal cancer were examined to clarify the clinicopathological significance of vascular endothelial growth factor (VEGF), thymidine phosphorylase (TP) and cluster of differentiation (CD)34 expression levels. VEGF expression was identified to be significantly correlated with TP expression (r=0.45; P<0.0001) and MVD in the high VEGF expression group was observed to be significantly greater than that in the low VEGF expression group (P=0.0194). In the Dukes' stage D group, the MVD in the high TP expression group was significantly greater than that in the low TP expression group (P=0.0149). High VEGF expression was subsequently correlated with a short overall survival rate for patients exhibiting lymph node metastasis (P=0.0128); however, there was no significant difference in overall survival rate regarding the expression levels of TP and CD34. The results of the present study indicate that VEGF expression may serve as a prognostic factor for colorectal cancer patients exhibiting lymph node metastasis. Furthermore, angiogenesis, as assessed by MVD, is an important prognostic factor for tumor growth at the primary site.

The plasminogen activator (PA) system consists of plasminogen activator inhibitor type 1 (PAI-1), urokinase-type plasminogen activator and its receptor (uPA and uPAR). PAI-1 inhibits the activation of uPA (which converts plasminogen to plasmin), and is involved in cancer invasion and metastasis, by remodeling the extracellular matrix (ECM) through regulating plasmin. Cancer stem cells (CSCs) are a small subset of cells within tumors, and are thought to be involved in tumor recurrence and metastasis. Considering these facts, we investigated the relationship between PAI-1 and cervical CSCs. We used ALDH1 as a marker of cervical CSCs. First, we demonstrated that culturing ALDH1-high cells and ALDH-low cells on collagen IV-coted plates increased their expression of active PAI-1 (ELISA), and these increases were suggested to be at mRNA expression levels (RT-qPCR). Secondly, we demonstrated PAI-1 was indeed involved in the ECM maintenance. With gelatin zymography assays, we found that ALDH1-high cells and ALDH-low cells expressed pro-matrix metalloproteinase-2 (pro-MMP-2) irrespective of their coatings. With gelatinase/collagenase assay kit, we confirmed that collagenase activity was increased when ALDH1-low cells were exposed to TM5275, a small molecule inhibitor of PAI-1. Putting the data together, we hypothesized that cancer cells adhered to basal membrane secrete abundant PAI-1, on the other hand, cancer cells (especially CSCs rather than non-CSCs) distant from basal membrane secrete less PAI-1, which makes the ECM surrounding CSCs more susceptible to degradation. Our study could be an explanation of conflicting reports, where some researchers found negative impacts of PAI-1 expression on clinical outcomes and others not, by considering the concept of CSCs.

Interleukin (IL)-36RN, previously known as IL1-F5 and IL-1δ, shares a 360-kb region of chromosome 2q13 with members of IL-1 systems. IL-36RN encodes an anti-inflammatory cytokine, IL-36 receptor antagonist (IL-36Ra). In spite of IL-36Ra showing the highest homology to IL-1 receptor (IL-1R) antagonist, it differs from the latter in aspects including its binding to IL-lRrp2 but not to IL-1R1. IL-36RN is mainly expressed in epithelial cells and has important roles in inflammatory diseases. In the present study, IL-36RN was identified in the genomes of 27 species, including human, chimpanzee, mouse, horse and dolphin. Human IL-36RN was mainly expressed in the eye, head and neck, fetal heart, lung, testis, cervix and placenta; furthermore, it was highly expressed in bladder and parathyroid tumors. Furthermore, a total of 30 single nucleotide polymorphisms causing missense mutations were determined, which are considered to be the causes of various diseases, such as generalized pustular psoriasis. In addition, the link between IL-36RN and the prognosis of certain cancer types was revealed through meta-analysis. Tumor-associated transcriptional factors c-Fos, activator protein-1, c-Jun and nuclear factor κB were found to bind to the upstream region in the IL-36RN gene. This may indicate that IL-36RN is involved in tumorigenesis and tumor progression through the regulation of tumor-associated transcriptional factors. The present study identified IL-36RN in various species and investigated the associations between IL-36RN and cancer prognosis, which would determine whether IL-36RN drove the evolution of the various species with regard to tumorigenesis.

To determine the expression of microRNA-210 (miR-210) in hepatocellular carcinoma (HCC) and to examine its role using HCC cells.

Results from the phase III TH3RESA study show that T-DM1 is effective in patients with metastatic HER2-positive breast cancer that has progressed despite two or more HER2-targeted therapies, extending their median overall survival by nearly 7 months.

The TP53-induced glycolysis and apoptosis regulator (TIGAR) is a p53 target gene known to regulate glycolysis by acting as fructose bis-phosphatase (FBPase) and modulate reactive oxygen species. TIGAR expression has been implicated in oncogenesis and progression of several human cancers. However, TIGAR expression is not known in various stages of colorectal cancer (CRC). There is an increase in the colorectal cancer incidence in Saudi Arabia. We sought to analyze TIGAR expression in this ethnic group. The aim of this study was to investigate the TIGAR expression in colorectal cancer (CRC) patients from Saudi Arabia. Tissue microarray (TMA) was constructed from 22 matched colorectal tumor tissues and adjacent normal tissues. TIGAR expression was examined in TMA slide using immunohistochemistry. TIGAR mRNA was determined in 14 matched tumor tissue and adjacent normal tissue. TIGAR protein expression was also examined in CRC tumor tissues and cell lines. Statistical analyses (t-test) were applied to evaluate the significance of TIGAR expression. TIGAR mRNA level was upregulated significantly in stage II (p<0.01) and stage III (p<0.05) when compared to adjacent normal tissue. Immunohistochemical studies revealed that TIGAR expression was increased in colorectal cancer. Strong TIGAR positive staining was found in 68% (15/22) of the tumor samples with nuclear localization. TIGAR staining was found to be significantly increased in early stage (stage I and II) CRC (p<0.05) and late stage (stage III and IV) CRC (p<0.01). TIGAR protein was also found to be highly expressed in stage II and III colorectal cancer tissues and CRC cell lines. These findings indicate that TIGAR is highly expressed at the mRNA and protein levels in colorectal cancer with prominent nuclear localization. TIGAR expression may be used as a bio-marker for detection of colorectal cancer and can be used as a target for developing therapeutics for the treatment of colorectal cancer.

In cancer immunotherapy, the use of dendritic cell (DC)-based vaccination strategies can improve overall survival, but until now durable clinical responses remain scarce. To date, DC vaccines are designed primarily to induce effective T-cell responses, ignoring the antitumor activity potential of natural killer (NK) cells. Aiming to further improve current DC vaccination outcome, we engineered monocyte-derived DC to produce interleukin (IL)-15 and/or IL-15 receptor alpha (IL-15Rα) using mRNA electroporation. The addition of IL-15Rα to the protocol, enabling IL-15 transpresentation to neighboring NK cells, resulted in significantly better NK-cell activation compared to IL-15 alone. Next to upregulation of NK-cell membrane activation markers, IL-15 transpresentation resulted in increased NK-cell secretion of IFN-γ, granzyme B and perforin. Moreover, IL-15-transpresenting DC/NK cell cocultures from both healthy donors and acute myeloid leukemia (AML) patients in remission showed markedly enhanced cytotoxic activity against NK cell sensitive and resistant tumor cells. Blocking IL-15 transpresentation abrogated NK cell-mediated cytotoxicity against tumor cells, pointing to a pivotal role of IL-15 transpresentation by IL-15Rα to exert its NK cell-activating effects. In conclusion, we report an attractive approach to improve antitumoral NK-cell activity in DC-based vaccine strategies through the use of IL-15/IL-15Rα mRNA-engineered designer DC.

To investigate the expression of HuR in pancreatic ductal adenocarcinoma (PDA) and to assess the effects of HuR silencing on the expression of cyclooxygenase-2 (COX-2) and heme oxygenase-1 (HO-1) and the in vitro response to gemcitabine (GEM) treatment in pancreatic cell lines.

Outcomes vary among patients with radioiodine refractory (RR) differentiated thyroid cancer (DTC). The prognostic factors for survival are not well-known, resulting in difficulty in selecting patients for new targeted therapies. We assessed overall survival (OS) and cancer-specific survival (CSS) from RR-DTC to identify prognostic factors associated with survival.

Additional research is needed to improve the ability to detect life-threatening cancer at an early curable stage and to prevent the development of such cancer. Many research groups are working to discover more effective and safer methods to detect and prevent life-threatening breast cancer. The results from such research studies will ultimately allow women’s expectations for breast cancer prevention and early detection to be met.

Recent research has highlighted a strong correlation between tissue-specific cancer risk and the lifetime number of tissue-specific stem-cell divisions. Whether such correlation implies a high unavoidable intrinsic cancer risk has become a key public health debate with the dissemination of the 'bad luck' hypothesis. Here we provide evidence that intrinsic risk factors contribute only modestly (less than ~10-30% of lifetime risk) to cancer development. First, we demonstrate that the correlation between stem-cell division and cancer risk does not distinguish between the effects of intrinsic and extrinsic factors. We then show that intrinsic risk is better estimated by the lower bound risk controlling for total stem-cell divisions. Finally, we show that the rates of endogenous mutation accumulation by intrinsic processes are not sufficient to account for the observed cancer risks. Collectively, we conclude that cancer risk is heavily influenced by extrinsic factors. These results are important for strategizing cancer prevention, research and public health.

Variant rs351855-G/A is a commonly occurring single-nucleotide polymorphism of coding regions in exon 9 of the fibroblast growth factor receptor FGFR4 (CD334) gene (c.1162G>A). It results in an amino-acid change at codon 388 from glycine to arginine (p.Gly388Arg) in the transmembrane domain of the receptor. Despite compelling genetic evidence for the association of this common variant with cancers of the bone, breast, colon, prostate, skin, lung, head and neck, as well as soft-tissue sarcomas and non-Hodgkin lymphoma, the underlying biological mechanism has remained elusive. Here we show that substitution of the conserved glycine 388 residue to a charged arginine residue alters the transmembrane spanning segment and exposes a membrane-proximal cytoplasmic signal transducer and activator of transcription 3 (STAT3) binding site Y(390)-(P)XXQ(393). We demonstrate that such membrane-proximal STAT3 binding motifs in the germline of type I membrane receptors enhance STAT3 tyrosine phosphorylation by recruiting STAT3 proteins to the inner cell membrane. Remarkably, such germline variants frequently co-localize with somatic mutations in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. Using Fgfr4 single nucleotide polymorphism knock-in mice and transgenic mouse models for breast and lung cancers, we validate the enhanced STAT3 signalling induced by the FGFR4 Arg388-variant in vivo. Thus, our findings elucidate the molecular mechanism behind the genetic association of rs351855 with accelerated cancer progression and suggest that germline variants of cell-surface molecules that recruit STAT3 to the inner cell membrane are a significant risk for cancer prognosis and disease progression.

Triple negative breast cancer (TNBC) accounts for approximately 15-20% of all types of breast cancer, and treatment is still limited. This type of breast cancer shows a high risk of recurrence, visceral metastasis, a worse prognosis, and shorter distant metastasis-free survival. Several studies have been reported that genetics factors are associated with breast cancer disease progression and patients' survival. In this study, we combined Taiwanese microarray data from the GEO database and The Cancer Genome Atlas (TCGA) database to study the role of Integrin Beta1 (ITGB1) in TNBC. Two triple negative breast cancer cell lines (MDA-MB-231; MDA-MB-468) were used to validate the functions of ITGB1. We found that a higher ITGB1 gene expression level was associated to lower survival. Silencing of ITGB1 inhibited TNBC cell migration, invasion and store-operated calcium influx. Our study provided a potential candidate biomarker for breast cancer cells migration, invasion and TNBC patients' survival.

In human cells ClpP and ClpX are imported into the mitochondrial matrix, where they interact to form the ATP-dependent protease ClpXP and play a role in the mitochondrial unfolded protein response. We find that reducing the levels of mitochondrial ClpP or ClpX renders human cancer cells more sensitive to cisplatin, a widely used anti-cancer drug. Conversely, overexpression of HClpP desensitizes cells to cisplatin. Overexpression of inactive HClpP-S97A had no effect. Cisplatin resistance correlated with decreased cellular accumulation of cisplatin and decreased levels of diguanosine-cisplatin adducts in both mitochondrial and genomic DNA. In contrast, higher levels of cisplatin-DNA adducts were found in cells in which HClpP had been depleted. Changes in the levels of ClpP had no effect on the levels of CTR1, a copper transporter that contributes to cisplatin uptake. However, the levels of ATP7A and ATP7B, copper efflux pumps that help eliminate cisplatin from cells, were increased when HClpP was overexpressed. HClpP levels were elevated in cervical carcinoma cells (KB-CP20) and hepatoma cells (BEL-7404-CP20) independently selected for cisplatin resistance. The data indicate that robust HClpXP activity positively affects the ability of cells to efflux cisplatin and suggest that targeting HClpP or HClpX would offer a novel mechanism for sensitizing cancer cells to cisplatin.