A novel microRNA-1207-3p/FNDC1/FN1/AR regulatory pathway in prostate cancer

Prostate cancer (PCa) is the second most common cause of cancer-specific deaths in the U.S. Unfortunately, the underlying molecular mechanisms for its development and progression remain unclear. Studies have established that microRNAs (miRNAs) are dysregulated in PCa. The intron-derived microRNA-1207-3p (miR-1207-3p) is encoded at the non-protein coding gene locus PVT1 on the 8q24 human chromosomal region, an established PCa susceptibility locus. However, miR-1207-3p in PCa had not previously been investigated. Therefore, we explored if miR-1207-3p plays any regulatory role in PCa. We discovered that miR-1207-3p is significantly underexpressed in PCa cell lines in comparison to normal prostate epithelial cells, and that increased expression of microRNA-1207-3p in PCa cells significantly inhibits proliferation, migration, and induces apoptosis via direct molecular targeting of fibronectin type III domain containing 1 (FNDC1). Our studies also revealed significant overexpression of FNDC1, fibronectin (FN1) and the androgen receptor (AR) in human PCa cell lines as well as tissues, and FNDC1, FN1, and AR positively correlate with aggressive PCa. These findings, recently published in Experimental Cell Research, are the first to describe a novel miR-1207-3p/FNDC1/FN1/AR novel regulatory pathway in PCa

Survivin Inhibition Is Critical for Bcl-2 Inhibitor-Induced Apoptosis in Hepatocellular Carcinoma Cells

Our study aims to study the therapeutic effects of a novel Bcl-2 inhibitor, ABT-263, on hepatocellular carcinoma (HCC) and to provide primary preclinical data for future clinical trial with ABT-263. In this study we showed that Bcl-xL and survivin were up-regulated in HCC cell lines and human liver cancer tissues. Clinic used ABT-263 single treatment had no apoptotic effects on HCC cells whereas higher doses of ABT-263 did. Interestingly, the combination treatment of ABT-263 with survivin inhibitor YM-155 could result in significant apoptosis in HCC cells. Survivin inhibition through gene silencing significantly enhanced ABT-263 to induce apoptosis in HCC cells. We found that low dose of ABT-263 single treatment resulted in ERK activation and survivin up-regulation, which might be involved in the resistance of HCC cells to ABT-263 since blockade of ERK activation sensitized ABT-263-induced apoptosis. Importantly, ABT-263 and YM-155 combination treatment had no apoptotic effects on normal human hepatocytes. Taken together, these data suggest the combination treatment of Bcl-2 inhibitor and survivin inhibition may have a great potential for liver cancer therapy

A novel microRNA-1207-3p/FNDC1/FN1/AR regulatory pathway in prostate cancer

Prostate cancer (PCa) is the second most common cause of cancer-specific deaths in the U.S. Unfortunately, the underlying molecular mechanisms for its development and progression remain unclear. Studies have established that microRNAs (miRNAs) are dysregulated in PCa. The intron-derived microRNA-1207-3p (miR-1207-3p) is encoded at the non-protein coding gene locus PVT1 on the 8q24 human chromosomal region, an established PCa susceptibility locus. However, miR-1207-3p in PCa had not previously been investigated. Therefore, we explored if miR-1207-3p plays any regulatory role in PCa. We discovered that miR-1207-3p is significantly underexpressed in PCa cell lines in comparison to normal prostate epithelial cells, and that increased expression of microRNA-1207-3p in PCa cells significantly inhibits proliferation, migration, and induces apoptosis via direct molecular targeting of fibronectin type III domain containing 1 (FNDC1). Our studies also revealed significant overexpression of FNDC1, fibronectin (FN1) and the androgen receptor (AR) in human PCa cell lines as well as tissues, and FNDC1, FN1, and AR positively correlate with aggressive PCa. These findings, recently published in Experimental Cell Research, are the first to describe a novel miR-1207-3p/FNDC1/FN1/AR novel regulatory pathway in PCa

Oxytocin and cancer: An emerging link

The neuropeptide hormone oxytocin, which is released from the posterior pituitary gland, is involved in a number of physiological processes. Understanding of its effects is gradually increasing due to new research in this area. While mostly recognized as a reproductive system hormone, oxytocin also regulates other organ systems such as the brain and cardiovascular system. Recently, research has focused on unraveling its involvement in cancer, and emerging evidence suggests a potential role for oxytocin as a cancer biomarker. This review summarizes observations linking oxytocin and cancer, with a special emphasis on prostate cancer, where it may promote cell proliferation. Research suggests that oxytocin effects may depend on cell type, concentration of the hormone, its interactions with other hormones in the microenvironment, and the precise localization of its receptor on the cell membrane. Future research is needed to further elucidate the involvement of oxytocin in cancer, and whether it could be a clinical cancer biomarker or therapeutic target

Leptin activates Akt in oesophageal cancer cells via multiple atorvastatin-sensitive small GTPases

Obesity is a risk factor for Barrett’s oesophagus and oesophageal adenocarcinoma. Adipose tissue secretes the hormone leptin. Leptin is a growth factor for several cell types, including Barrett’s cells and oesophageal adenocarcinoma cells. Statins are associated with reduced rates of Barrett’s oesophagus and oesophageal cancer and exhibit anti-cancer effects in vitro. The mechanisms of these effects are not fully established. We have examined the effects of leptin and the lipid-soluble statin, atorvastatin, on signalling via monomeric GTP-binding proteins and Akt. Proliferation and apoptosis were assessed in OE33 cells. Akt activity was quantified by cell-based ELISA and in vitro kinase assay. Specific small-molecule inhibitors and a dominant-negative construct were used to reduce Akt activity. Small GTPases were inhibited using transfection of dominant-negative plasmids, prenylation inhibitors and pretreatment with atorvastatin. Leptin stimulated Akt activity and cell proliferation and inhibited camptothecin-induced apoptosis in an Akt-sensitive manner. Leptin induced phosphorylation of Bad and FOXO1 in an Akt-sensitive manner. Leptin activated Ras, Rac, RhoA and cdc42. Transfection of dominant-negative plasmids confirmed that leptin-induced Akt activation required Ras, RhoA cdc42 but not Rac. Atorvastatin inhibited leptin-induced activation of Ras, RhoA, cdc42 and Akt. Co-treatment with mevalonate prevented these effects of atorvastatin. The protein kinase Akt is essential to the growth-promoting and anti-apoptotic effects of leptin in oesophageal adenocarcinoma cells. Akt is activated via Ras-, Rho- and cdc42-dependant pathways. Atorvastatin reduces leptin-induced Akt activation by inhibiting prenylation of small GTPases. This may explain the reduced incidence of oesophageal adenocarcinoma in statin-users

Fibronectin and androgen receptor expression data in prostate cancer obtained from a RNA-sequencing bioinformatics analysis

Prostate cancer is the second most commonly diagnosed male cancer in the world. The molecular mechanisms underlying its development and progression are still unclear. Here we show analysis of a prostate cancer RNA-sequencing dataset that was originally generated by Ren et al. [3] from the prostate tumor and adjacent normal tissues of 14 patients. The data presented here was analyzed using our RNA-sequencing bioinformatics analysis pipeline implemented on the bioinformatics web platform, Galaxy. The relative expression of fibronectin (FN1) and the androgen receptor (AR) were calculated in fragments per kilobase of transcript per million mapped reads, and represented in FPKM unit. A subanalysis is also shown for data from three patients, that includes the relative expression of FN1 and AR and their fold change. For interpretation and discussion, please refer to the article, “miR-1207-3p regulates the androgen receptor in prostate cancer via FNDC1/fibronectin” [1] by Das et al

PVT1 Exon 9: A Potential Biomarker of Aggressive Prostate Cancer?

Prostate cancer (PCa) is the most commonly diagnosed cancer as well as the greatest source of cancer-related mortality in males of African ancestry (MoAA). Interestingly, this has been shown to be associated with single nucleotide polymorphisms around regions 2 and 3 of the 8q24 human chromosomal region. The non-protein coding gene locus Plasmacytoma Variant Translocation 1 (PVT1) is located at 8q24 and is overexpressed in PCa and, therefore, is also a candidate biomarker to explain the well-known disparity in this group. PVT1 has at least 12 exons that make separate transcripts which may have different functions, all of which are at present unknown in PCa. Our aim was to determine if any PVT1 transcripts play a role in aggressiveness and racial disparity in PCa. We used a panel of seven PCa cell lines including three derived from MoAA. Ribonucleic acid extraction, complementary deoxyribonucleic acid synthesis, and quantitative polymerase chain reaction (qPCR) were performed to evaluate expression of all 12 PVT1 exons. Each qPCR was performed in quadruplicates. At least four separate qPCR experiments were performed. Expression of PVT1 exons was inconsistent except for exon 9. There was no significant difference in exon 9 expression between cell lines derived from Caucasian males (CM), and an indolent cell line derived from MoAA. However, exon 9 expression in the aggressive MDA PCa 2b and E006AA-hT cell lines derived from MoAA was significantly higher than in other cell lines. Consequently, we observed differential expression of exon 9 of PVT1 in a manner that suggests that PVT1 exon 9 may be associated with aggressive PCa in MoAA

miR-1207-3p Is a Novel Prognostic Biomarker of Prostate Cancer

MicroRNAs (miRNAs) have been found to be dysregulated in prostate cancer (PCa). In this study, we investigated if miR-1207-3p is capable of distinguishing between indolent and aggressive PCa and if it contributes to explaining the disproportionate aggressiveness of PCa in men of African ancestry (moAA). A total of 404 patients with primary adenocarcinoma of the prostate were recruited between 1988 and 2003 at the Moffitt Cancer Center, Tampa, FL, USA. Patient clinicopathological features and demographic characteristics such as race were identified. RNA samples from 404 postprostatectomy prostate tumor tissue samples were analyzed by real-time quantitative reverse transcription polymerase chain reaction for the mRNA expression of miR-1207-3p. miR-1207-3p expression in PCa that resulted in overall death or PCa-specific death is significantly higher than in PCa cases that did not. The same positive correlation holds true for other clinical characteristics such as biochemical recurrence, Gleason score, clinical stage, and prostate-specific antigen level. Furthermore, miR-1207-3p expression was significantly less in moAA in comparison to Caucasian men. We also evaluated whether miR- 1207-3p is associated with clinical outcomes adjusted for age at diagnosis and tumor stage in the modeling. Using competing risk regression, the PCa patients with a high miR-1207-3p expression (≥6 vs 3) had a high risk to develop PCa recurrence (hazard rate = 2.5, P b .001) adjusting for age at diagnosis and tumor stage. In conclusion, miR-1207-3p is a promising novel prognostic biomarker for PCa. Furthermore, miR-1207-3p may also be important in explaining the disproportionate aggressiveness of PCa in moAA

Mechanisms of hepatocellular carcinoma progression

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. It is the second leading cause of cancer-related deaths worldwide, with a very poor prognosis. In the United States, there has been only minimal improvement in the prognosis for HCC patients over the past 15 years. Details of the molecular mechanisms and other mechanisms of HCC progression remain unclear. Consequently, there is an urgent need for better understanding of these mechanisms. HCC is often diagnosed at advanced stages, and most patients will therefore need systemic therapy, with sorafenib being the most common at the present time. However, sorafenib therapy only minimally enhances patient survival. This review provides a summary of some of the known mechanisms that either cause HCC or contribute to its progression. Included in this review are the roles of viral hepatitis, non-viral hepatitis, chronic alcohol intake, genetic predisposition and congenital abnormalities, toxic exposures, and autoimmune diseases of the liver. Well-established molecular mechanisms of HCC progression such as epithelial-mesenchymal transition, tumor-stromal interactions and the tumor microenvironment, cancer stem cells, and senescence bypass are also discussed. Additionally, we discuss the roles of circulating tumor cells, immunomodulation, and neural regulation as potential new mechanisms of HCC progression. A better understanding of these mechanisms could have implications for the development of novel and more effective therapeutic and prognostic strategies, which are critically needed