Prognostic value of high mobility group protein A2 (HMGA2) over-expression in cancer progression

The high mobility group A2 (HMGA2; also called HMGI-C) gene is an architectural transcription factor that belonging to the high mobility group AT-hook (HMGA) gene family. HMGA2 is aberrantly regulated in several human tumors. Over-expression of HMGA2 is correlated with a higher risk of metastasis and an unfavorable prognosis in patients with cancer. We performed a meta-analysis to determine the clinic-pathological and prognostic value of HMGA2 overexpression in different human tumors. A comprehensive literature search was performed using PubMed, Embase, Cochrane Library, Scopus, MEDLINE, Google Scholar and ISI Web of Science. Hazard ratios (HRs)/odds ratios (ORs) and their 95% confidence intervals (CIs) were used to assess the strength of the association between HMGA2 expression and overall survival (OS)/progression free survival (PFS)/disease free survival (DFS). A total of 5319 patients with 19 different types of cancer from 35 articles were evaluated. Pooled data analysis indicated that increased HMGA2 expression in cancer patients predicted a poor OS (HR = 1.70; 95% CI = 1.6–1.81; P < 0.001; fixed-effect model). In subgroup analyses, high HMGA2 expression was particularly associated with poor OS in individuals with gastrointestinal (GI) cancer (HR = 1.89, 95% CI: 1.83–1.96; fixed-effect model) and HNSCC cancer (HR-1.78, 95%CI: 1.44–2.21; fixed-effect model). Over-expression of HMGA2 was associated with vascular invasion (OR = 0.16, 95% CI = 0.05–0.49; P = 0.001) and lymphatic invasion (OR = 1.89, 95% CI = 1.06–3.38; P = 0.032). Further studies should be conducted to validate the prognostic value of HMGA2 for patients with GI cancers

Crocin synergistically enhances the anti-proliferative activity of 5-FU through Wnt/PI3K pathway in a mouse model of colitis-associated colorectal cancer

Colorectal-cancer (CRC) is the third most common cause of cancer-related-death, and hence there is a need for the identification of novel-agents to improve the efficacy of existing-therapies. There is growing evidence for the anti-tumor-activity of crocin, although its activity and molecular-mechanisms in CRC remains to be elucidated. Here we explored the therapeutic-application of crocin or its combination with 5-Flurouracil in a mouse-model of colitis-associated colon-cancer. The anti-proliferative-activity of crocin was assessed in 2- and 3-dimensional cell-culture-models. The migratory-behaviors were determined, while the expression-levels of several-genes were assessed by qRT-PCR/Western-blotting. We examined the anti-inflammatory properties of crocin by pathological-evaluation and disease-activity-index as well as oxidative/ antioxidant markers: malondialdehyde (MDA) and total-thiols (T-SH) levels and superoxide-dismutase (SOD) and catalase (CAT) activity. Crocin suppressed cell-growth and the invasive-behavior of CRC-cells through modulation of the Wnt-pathway and E-cadherin. Moreover, administration of crocin alone, or in combination with 5-FU dramatically reduced the tumor-number and tumor-size in both distal/mid-colon followed by reduction in disease-activity-index. Crocin also suppressed the colonic-inflammation induced by Dextran-sulfate-sodium and notably recovered the increased-levels of MDA, decreased Thiol-levels and activity of CAT-levels. Crocin was able to ameliorate the severe-inflammation with mucosal-ulcers and high grade-dysplastic-crypts as detected by inflammation-score, Crypt-loss, pathological-changes and histology-scores. We demonstrated an antitumor-activity of crocin in CRC and its potential role in improvement of inflammation with mucosal ulcers and high grade dysplastic crypts, supporting the desireability of further investigations on the therapeutic potential of this approach in CRC

The prognostic value of long noncoding RNA MEG3 expression in the survival of cancer patients: a meta-analysis

Long non-coding RNAs (lncRNAs) play an important role in carcinogenesis and cancer progression. lncRNA MEG3 is a tumor suppressor that is down-regulated in several cancers. However, its prognostic value in human malignancies remains controversial. We have therefore undertaken a meta-analysis to explore the relationship between cancer survival and the expression of long non-coding RNA MEG3. A systematic literature search identified 13 potentially eligible investigations comprising 1733 patients in nine different cancer types. In the pooled analysis, a low expression of MEG3 was associated with a low overall survival (OS) in cancer patients with a combined HR of 0.830 [hazard ratio (HR) =0.83; 95% CI: 0.70–0.98; P=0.0.03; random effect model]. However, sub-group analysis according to cancer type revealed that MEG3 expression was not associated with better OS in gastrointestinal cancer (HR = 0.58, 95% CI = 0.33 to 1.03, P = 0.06) and breast cancer patients (HR = 0.85, 95% CI: 0.12 to 5.88, P = 0.87). In conclusion, our results demonstrate that only in the pooled analysis, there was a significant relationship between MEG3 expression and cancer survival. Further investigation of other molecular biomarkers involved in tumorigenesis-related pathways is necessary

The interaction between a HSP-70 gene variant with dietary calories in determining serum markers of inflammation and cardiovascular risk

Background: The high prevalence of cardiovascular disease (CVD) globally is attributable to an interaction between environmental and genetic factors. Gene × diet interaction studies aim to explore how a modifiable factor interacts with genetic predispositions. Here we have explored the interaction of a heat shock protein (HSP70) gene polymorphism (+1267A>G) with dietary intake and their possible association with serum C-reactive protein (CRP), an inflammatory marker, that is a major component of CVD risk. Methods: HSP70 genotype was determined using a TaqMan real time PCR based method. Genetic variation of the HSP70 gene +1267A>G locus. Dietary intake was assessed using a dietary questionnaire. Serum high sensitivity (Hs) CRP and other cardiovascular risk factors were assessed by routine methods. This included coronary angioplasty to determine the presence of coronary artery stenosis. Results: There were significant differences between serum lipid profile and Hs-CRP across the genotypes for Hsp70. The carriers of G allele had higher serum hs-CRP concentrations, compared with the AA homozygotes, with the wild genotype. Interaction analysis showed the association was modulated by total energy intake; the interaction of high energy intake with GG genotype: RERI= 0.77, AP= 0.26, S=1.6. Conclusion: We have found a significant association between the +1267A>G variant of the HSP70 gene with cardiovascular risk factors and serum hs-CRP concentrations. It is possible that a low energy diet could ameliorate the unfavorable effects of G allele of HSP70

The diagnostic, prognostic and therapeutic potential of circulating microRNAs in ovarian cancer

Ovarian cancer (OC) is often diagnosed at an advanced stage because of the late onset of symptoms, and this together with the lack of effective treatments, has meant it is associated with a very high mortality. The aberrant expression of MicroRNA (miRNA) contributes to the initiation and development of human tumors including OC. Several miRNAs are secreted by tumor cells and can be identified in body fluids. Serum miRNAs levels are associated with several clinical conditions, and may be used to predict prognosis and response to treatments in some cancers including OC. This review summarizes the current progresses regarding the potential applications of circulating miRNA as innovative biomarkers in OC

A genetic polymorphism in the CYP1B1 gene in patients with squamous cell carcinoma of the esophagus: an Iranian Mashhad cohort study recruited over 10 years

Background: Esophageal-cancer is the seventh most common-cause of cancer-related-deaths in men. Cytochrome-P450-family-1-subfamily-B-polypeptide-1 (CYP1B1) plays a role in the metabolism of xenobiotics, and is associated with several cancers. Here we investigated the association between a genetic-variant, CYP1B1-rs1056836, with the clinical-characteristics of patients with esophagus-squamous-cell-carcinoma (ESCC). Method: 117-patients with ESCC and 208 healthy-subjects were recruited. DNA was extracted and genotyped. Kaplan-Meier curves were utilized to assess overall and progression-free survival. The relationship between clinicopathological-data, disease-prognosis, and survival, were evaluated with the genotypes. Results: the genotypic frequency for GG, GC, and CC were 58.6%, 29.8%, 11.5% respectively in the healthy subjects and 51.8%, 36.14% and 12% in the ESCC group. An association between the GG genotype and stage of ESCC was found. Conclusion: Our findings suggest a relationship between the CYP1B1-rs1056836 genetic polymorphism and clinical features of ESCC, supporting further studies in larger-populations in different-ethnic groups, taking into account potentially important environmental-factors

Angiotensin receptor blocker losartan inhibits tumor growth of colorectal cancer

The renin-angiotensin system (RAS) is up-regulated in patients with colorectal cancer (CRC) and is reported to be associated with poor prognosis and chemo-resistance. Here we explored the therapeutic potential of targeting RAS in CRC using Losartan, an angiotensin receptor blocker. An integrative-systems biology approach was used to explore a proteome-level dataset of a gene signature that is modulated by Losartan. The anti-proliferative activity of Losartan was evaluated using 2- and 3-dimensional cell culture models. A xenograft model of colon cancer was used to investigate tumor growth with Losartan alone and in combination with 5-FU followed by histological staining (Hematoxylin & Eosin and Masson trichrome staining), biochemical analyses, gene expression analyses by RT-PCR, western blot/IHC, or MMP Gelatin Zymography studies. Effects on cell cycle and cell death were assessed by flow cytometry. Losartan inhibited cell growth and suppressed cell cycle progression, causing an increase in CRC cells in the G1 phase. Losartan significantly reduced tumor growth and enhanced tumor cell necrosis. An impact on the inflammatory response, including up-regulation of pro-inflammatory cytokines and chemokines in CRC cells are potential mechanisms that could partially explain Losartan’s anti-proliferative effects. Moreover, metastasis and angiogenesis were reduced in Losartan-treated mice as observed by inhibited matrix metalloproteinase-2 and -9 activities and decreased tumor vasculature. These data demonstrate the therapeutic potential of combining chemotherapeutic regimens with Losartan to synergistically enhance its activity and target the renin-angiotensin system as a new approach in colorectal cancer treatment

Cyclin Dependent Kinase-1 (CDK-1) Inhibition as a Novel Therapeutic Strategy against Pancreatic Ductal Adenocarcinoma (PDAC)

The role of CDK1 in PDAC onset and development is two-fold. Firstly, since CDK1 activity regulates the G2/M cell cycle checkpoint, overexpression of CDK1 can lead to progression into mitosis even in cells with DNA damage, a potentially tumorigenic process. Secondly, CDK1 overexpression leads to the stimulation of a range of proteins that induce stem cell properties, which can contribute to the development of cancer stem cells (CSCs). CSCs promote tumor-initiation and metastasis and play a crucial role in the development of PDAC. Targeting CDK1 showed promising results for PDAC treatment in different preclinical models, where CDK1 inhibition induced cell cycle arrest in the G2/M phase and led to induction of apoptosis. Next to this, PDAC CSCs are uniquely sensitive to CDK1 inhibition. In addition, targeting of CDK1 has shown potential for combination therapy with both ionizing radiation treatment and conventional chemotherapy, through sensitizing tumor cells and reducing resistance to these treatments. To conclude, CDK1 inhibition induces G2/M cell cycle arrest, stimulates apoptosis, and specifically targets CSCs, which makes it a promising treatment for PDAC. Screening of patients for CDK1 overexpression and further research into combination treatments is essential for optimizing this novel targeted therapy

Clinical practice guidelines for interventional treatment of pancreatic cancer

Pancreatic cancer (PC) usually has a poor prognosis; it is rarely detected at an early stages, by which time it has often spread locally, or metastasized. There are several types of PCs, but the most common is pancreatic adenocarcinoma that comprises 85% of cases. Adenocarcinomas develop in areas of the exocrine gland, that secrete digestive enzymes. About 1%-2% of PCs arise in the nerves and endocrine gland. In generally, the aggressiveness of the latter tumors is less than for those developing in the exocrine pancreas.</p