Showing papers in "Tumor Biology in 2015"
TL;DR: Results suggested that LINC00152 can be detected in plasma, and one of the possible mechanisms of its stable existence in blood was protected by exosomes.
Abstract: Long intergenic non-protein-coding RNA 152 (LINC00152) is one of the long noncoding RNAs (lncRNAs) abnormally expressed in gastric cancer tissues. However, its value in the diagnosis of gastric cancer is unclear. The aim of this study is to evaluate the clinical significance of plasma LINC00152 as a biomarker in the screening of gastric cancer and to explore the possible mechanism underling its stable existence in blood. We analyzed the levels of plasma LINC00152 in patients with gastric cancer and gastric epithelial dysplasia and healthy controls using quantitative reverse transcription polymerase chain reaction and then confirmed by sequencing. We also compared its levels in paired preoperative and postoperative plasma samples. In addition, we compared the levels of LINC00152 in plasma and in exosomes, which were extracted from the same plasma and confirmed by transmission electron microscopy. The levels of plasma LINC00152 were significantly elevated in gastric cancer patients compared with healthy controls. The sensitivity and specificity of plasma LINC00152 in the diagnosis of gastric cancer were 48.1 and 85.2%, respectively. There were no significant differences of LINC00152 levels between gastric epithelial dysplasia patients and healthy controls. LINC00152 levels in preoperative plasma samples were lower than those in postoperative ones. There were also no differences between LINC00152 levels in plasma and in exosomes. All these results suggested that LINC00152 can be detected in plasma, and one of the possible mechanisms of its stable existence in blood was protected by exosomes. It has the possibility to be applied in gastric cancer diagnosis as a novel blood-based biomarker.
335 citations
TL;DR: The findings indicated that MALAT1 might suppress the tumor growth and metastasis via PI3K/AKT signaling pathway and could be regarded as a therapeutic target in human osteosarcoma.
Abstract: Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), one of the first found cancer-associated long noncoding RNAs (lncRNAs), involves in the development and progression of many types of tumors An aberrant expression of MALAT1 was observed in hepatocellular carcinoma, cervical cancer, breast cancer, ovarian cancer, and colorectal cancer However, the exact effects and molecular mechanisms of MALAT1 in osteosarcoma progression are still unknown up to now Here, we investigated the role of MALAT1 in human osteosarcoma cell lines and clinical tumor samples in order to determine the function of this molecule In our research, the MALAT1 messenger RNA (mRNA) was highly expressed in human osteosarcoma tissues, and its expression level was closely correlated with pulmonary metastasis Then, we employed lentivirus-mediated knockdown of MALAT1 in U-2 OS and SaO2 to determine the role of MALAT1 in osteosarcoma cell lines Lentivirus-mediated MALAT1 small interfering RNA (siRNA) could efficiently downregulated the expression level of MALAT1 in osteosarcoma cell lines Knockdown of MALAT1 inhibited the proliferation and invasion of human osteosarcoma cell and suppressed its metastasis in vitro and vivo At the same time, the proliferating cell nuclear antigen (PCNA), matrix metallopeptidase 9 (MMP-9), phosphorylated PI3Kp85α, and Akt expressions were significantly inhibited in MALAT1-deleted cells These findings indicated that MALAT1 might suppress the tumor growth and metastasis via PI3K/AKT signaling pathway Taken together, our data indicated that MALAT1 might be an oncogenic lncRNA that promoted proliferation and metastasis of osteosarcoma and could be regarded as a therapeutic target in human osteosarcoma
269 citations
TL;DR: The data suggested that lncRNA MALAT1 was a novel molecule involved in ccRCC progression, which provided a potential prognostic biomarker and therapeutic target and indicated that knockdown expression of MALat1 decreased renal cancer cell proliferation, migration, and invasion.
Abstract: Long noncoding RNAs (lncRNAs) have been investigated as a new class of regulators of cellular processes, such as cell growth, apoptosis, and carcinogenesis. LncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has recently been identified to be involved in tumorigenesis of several cancers such as lung cancer, pancreatic cancer, and cervical cancer. However, the role of lncRNA MALAT1 in clear cell renal cell carcinoma (ccRCC) remains unclear. Expression levels of lncRNA MALAT1 in ccRCC tissues and renal cancer cell lines were evaluated by quantitative real-time PCR (qRT-PCR), and its association with overall survival of patients was analyzed by statistical analysis. Small interfering RNA (siRNA) was used to suppress MALAT1 expression in renal cancer cells. In vitro assays were conducted to further explore its role in tumor progression. The expression level of MALAT1 was higher in ccRCC tissues and renal cancer cells compared to adjacent non-tumor tissues and normal human proximal tubule epithelial cells HK-2. The ccRCC patients with higher MALAT1 expression had an advanced clinical features and a shorter overall survival time than those with lower MALAT1 expression. And multivariate analysis showed that the status of MALAT1 expression was an independent predictor of overall survival in ccRCC. Additionally, our data indicated that knockdown expression of MALAT1 decreased renal cancer cell proliferation, migration, and invasion. Our data suggested that lncRNA MALAT1 was a novel molecule involved in ccRCC progression, which provided a potential prognostic biomarker and therapeutic target.
193 citations
TL;DR: It is found that lncRNA MALAT1 overexpression was an unfavorable prognostic factor in pancreatic cancer patients, regardless of clinical stage, tumor size, lymph node metastasis, and distant metastasis.
Abstract: Long non-coding RNAs (lncRNAs) have been proved to serve as a critical role in cancer development and progression. However, little is known about the pathological role of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in pancreatic cancer patients. The aims of this study are to measure the expression of lncRNA MALAT1 in pancreatic cancer patients and to explore the clinical significance of the lncRNA MALAT1. Using qRT-PCR, the expression of lncRNA MALAT1 was measured in 126 pancreatic cancer tissues and 15 adjacent non-cancerous tissues. In the present study, our results indicated that lncRNA MALAT1 was highly expressed in pancreatic cancer compared with adjacent non-cancerous tissues (P < 0.001), and positively correlated with clinical stage (early stages vs. advanced stages, P < 0.001), tumor size (<2 vs. ≥2 cm, P = 0.004), lymph node metastasis (negative vs. positive, P < 0.001), and distant metastasis (absent vs. present, P = 0.001) in pancreatic cancer patients. Furthermore, we also found that lncRNA MALAT1 overexpression was an unfavorable prognostic factor in pancreatic cancer patients (P < 0.001), regardless of clinical stage, tumor size, lymph node metastasis, and distant metastasis. Finally, increased lncRNA MALAT1 expression was an independent poor prognostic factor for pancreatic patients through multivariate analysis (P = 0.018). In conclusion, overexpression of lncRNA MALAT1 serves as an unfavorable prognostic biomarker in pancreatic cancer patients.
173 citations
TL;DR: A novel perspective would be produced to make clear cancer mechanisms and suggest novel approaches to regulate ceRNA networks via miRNA competition for cancer therapeutics through sponging microRNAs in these pathways.
Abstract: Competing endogenous RNAs (ceRNAs) are RNA transcripts which can communicate with each other by decreasing targeting concentration of micro-RNA (miRNA) with the derepression of other messenger RNAs (mRNAs) having the common miRNA response elements (MREs). Oncocers are ceRNAs taking crucial roles in oncogenic pathways processed in many types of cancer, and this study analyzes oncocer-mediated cross-talk by sponging microRNAs (miRNAs) in these pathways. While doing this, breast, liver, colon, prostate, gastric, lung, endometrium, thyroid and epithelial cancers and melanoma, rhabdomyosarcoma, glioblastoma, acute promyelocytic leukemia, retinoblastoma, and neuroblastoma were analyzed with respect to ceRNA-based carcinogenesis. This study defines, firstly, oncocers in the literature and contains all oncocer-related findings found up to now. Therefore, it will help to increase our comprehension about oncocer-mediated mechanisms. Via this study, a novel perspective would be produced to make clear cancer mechanisms and suggest novel approaches to regulate ceRNA networks via miRNA competition for cancer therapeutics.
154 citations
TL;DR: In this article, the role of lncRNA MALAT1 in the pathogenesis of glioma was identified and the relationship of LncRNA mALAT 1 expression with clinicopathological characteristics was analyzed.
Abstract: The metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a bona fide long noncoding RNA (lncRNA). LncRNA MALAT1 was discovered as a prognostic factor for lung cancer metastasis but also has been linked to several other human tumor entities. However, little is known about the role of lncRNA MALAT1 in glioma patients. The aim of this study was to identify the role of lncRNA MALAT1 in the pathogenesis of glioma; we analyzed the relationship of lncRNA MALAT1 expression with clinicopathological characteristics in glioma patients. In our results, lncRNA MALAT1 expression was increased in glioma tissues compared with paired adjacent brain normal tissues (P < 0.001). Furthermore, lncRNA MALAT1 was associated significantly with WHO grade (I–II vs. III–IV; P = 0.007) and tumor size (<3 cm vs. T ≥ 3 cm; P = 0.008). However, lncRNA MALAT1 expression was not associated significantly with age (<45 vs. ≥45, P = 0.343), gender (female vs. male, P = 0.196), family history of cancer (yes vs. no, P = 0.665), and tumor location (supratentorial vs. infratentorial, P = 0.170). Moreover, the level of lncRNA MALAT1 expression was markedly correlated with the glioma patients’ overall survival (P < 0.001). Multivariate analysis suggested that increased lncRNA MALAT1 expression was a poor independent prognostic predictor for glioma patients (P = 0.002). In conclusion, lncRNA MALAT1 plays an important role on glioma progression and prognosis and may serve as a convictive prognostic biomarker for glioma patients.
150 citations
TL;DR: The expression profile of taurine-upregulated gene 1 (TUG1), a lncRNA recruiting and binding to polycomb repressive complex 2 (PRC2), in ESCC is characterized and indicates that TUG1 promotes proliferation and migration of ES CC cells and is a potential oncogene of ESCC.
Abstract: Esophageal squamous cell carcinoma (ESCC) is one of the prevalent and deadly cancers worldwide, especially in Eastern Asia. The prognosis of ESCC remains poor; thus, it is still necessary to further dissect the underlying mechanisms and explore therapeutic targets of ESCC. Recent studies show that long noncoding RNAs (lncRNAs) have critical roles in diverse biological processes, including tumorigenesis. Some lncRNAs, such as HOTAIR and POU3F3, were reported to play important roles in ESCC. Here, we characterized the expression profile of taurine-upregulated gene 1 (TUG1), a lncRNA recruiting and binding to polycomb repressive complex 2 (PRC2), in ESCC. In a cohort of 62 patients, TUG1 was significantly overexpressed in ESCC tissues compared with paired adjacent normal tissues, and high expression level of TUG1 was associated with family history and upper segment of esophageal cancer (p < 0.05). Further, in vitro silencing TUG1 via siRNA inhibited the proliferation and migration of ESCC cells and blocked the progression of cell cycle. Therefore, our study indicates that TUG1 promotes proliferation and migration of ESCC cells and is a potential oncogene of ESCC.
146 citations
TL;DR: Both total and antigen-specific count of MVs significantly correlated with different HM clinical features such as Rai stage in CLL, International Prognostic Scoring System in WM, International Staging System in MM, and clinical stage in HL.
Abstract: Many cell types release extracellular vesicles (EVs), including exosomes, microvesicles (MVs), and apoptotic bodies, which play a role in physiology and diseases. Presence and phenotype of circulating EVs in hematological malignancies (HMs) remain largely unexplored.The aim of this study was to characterize EVs in peripheral blood of HM patients compared to healthy subjects (controls). We isolated serum EVs from patients with chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), Waldenstrom's macroglobulinemia (WM), Hodgkin's lymphoma (HL), multiple myeloma (MM), acute myeloid leukemia (AML), myeloproliferative neoplasms (MPNs), myelodysplastic syndromes (MDS), and controls. EVs were isolated from serum of peripheral blood by ultracentrifuge steps and analyzed by flow cytometry to define count, size, and immunophenotype. MV levels were significantly elevated in WM, HL, MM, AML, and some MPNs and, though at a lesser degree, in CLL and NHL as compared to healthy controls. HL, MM, and MPNs generated a population of MVs characterized by lower size (below 0.3 μm) when compared to controls. MVs from patients specifically expressed tumor-related antigens, such as CD19 in B cell neoplasms, CD38 in MM, CD13 in myeloid tumors, and CD30 in HL. Both total and antigen-specific count of MVs significantly correlated with different HM clinical features such as Rai stage in CLL, International Prognostic Scoring System in WM, International Staging System in MM, and clinical stage in HL. MVs may represent a novel biomarker in HMs.
142 citations
TL;DR: It is demonstrated that M EG3 is involved in the development and progression of colorectal cancer by regulating cell proliferation and shows that MEG3 may be a potential diagnostic and prognostic target in patients with coloreCTal cancer.
Abstract: Colorectal cancer (CRC) remains an important public health problem in the world. Long noncoding RNA (lncRNA) is an RNA molecular that is longer than 200 nucleotides and cannot be translated into a protein. Recent studies have shown that lncRNAs play important roles in carcinogenesis and cancer metastasis. The aim of this study was to evaluate the expression and biological role of lncRNA maternally expressed gene 3 (MEG3) in colorectal cancer. Quantitative real-time-PCR (qRT-PCR) was performed to investigate the expression of MEG3 in tumor tissues and corresponding nontumor colorectal tissues from 62 patients. The lower expression of MEG3 was remarkably correlated with low histological grade, deep tumor invasion, and advanced tumor node metastasis (TNM) stage. Multivariate analyses revealed that MEG3 expression served as an independent predictor for overall survival. Further experiments revealed that overexpressed MEG3 significantly inhibited CRC cell proliferation both in vitro and in vivo. In conclusion, our study demonstrated that MEG3 is involved in the development and progression of colorectal cancer by regulating cell proliferation and shows that MEG3 may be a potential diagnostic and prognostic target in patients with colorectal cancer.
140 citations
TL;DR: This study provides direct evidence that the improved survival in patients with IDH1-R132H tumors may partly result from the effects of the IDH2-R131H protein on chemosensitivity, including the GSH depletion and increased ROS generation.
Abstract: Gliomas are the most malignant and aggressive primary brain tumor in adults. Despite concerted efforts to improve therapies, their prognosis remains very poor. Isocitrate dehydrogenase 1 (IDH1) mutations have been discovered frequently in glioma patients and are strongly correlated with improved survival. However, the effect of IDH1 mutations on the chemosensitivity of gliomas remains unclear. In this study, we generated clonal U87 and U251 glioma cell lines overexpressing the R132H mutant protein (IDH1-R132H). Compared with control cells and cells overexpressing IDH wild type (IDH1-WT), both types of IDH1-R132H cells were more sensitive to temozolomide (TMZ) and cis-diamminedichloroplatinum (CDDP) in a time- and dose-dependent manner. The IDH1-R132H-induced higher chemosensitivity was associated with nicotine adenine disphosphonucleotide (NADPH), glutathione (GSH) depletion, and reactive oxygen species (ROS) generation. Accordingly, this IDH1-R132H-induced growth inhibition was effectively abrogated by GSH in vitro and in vivo. Our study provides direct evidence that the improved survival in patients with IDH1-R132H tumors may partly result from the effects of the IDH1-R132H protein on chemosensitivity. The primary cellular events associated with improved survival are the GSH depletion and increased ROS generation.
118 citations
TL;DR: This review tries to give readers a concise and reliable illustration on the mechanism, functions, research approaches, and perspective of ceRNA in cancer.
Abstract: Competing endogenous RNAs (ceRNAs) refer to RNA transcripts, such as mRNAs, non-coding RNAs, pseudogene transcripts, and circular RNAs, that can regulate each other by competing for the same pool of miRNAs. ceRNAs involve in the pathogenesis of several common cancers such as prostate cancer, liver cancer, breast cancer, lung cancer, gastric cancer, endometrial cancer, and so on. ceRNA activity is determined by factors such as miRNA/ceRNA abundance, ceRNAs binding affinity to miRNAs, RNA editing, and RNA-binding proteins. The alteration of any of these factors may lead to ceRNA network imbalance and thus contribute to cancer initiation and progression. There are generally three steps in ceRNA research conductions: ceRNA prediction, ceRNA validation, and ceRNA functional investigation. Deciphering ceRNA interplay in cancer provides new insight into cancer pathogenesis and opportunities for therapy exploration. In this review, we try to give readers a concise and reliable illustration on the mechanism, functions, research approaches, and perspective of ceRNA in cancer.
TL;DR: This review has gathered results from in vivo experiments, presenting the use of statins in combined therapies and discussed a number of molecular targets that could serve as biomarkers predisposing to statin therapy.
Abstract: Statins [3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase, abbreviated HMGCR) inhibitors], are well-known cholesterol-depleting agents. Since the early 1990s, it has been known that statins could be successfully used in cancer therapy, but the exact mechanism(s) of statin activity remains unclear and is now an extensive focus of investigation. So far, it was proven that there are several mechanisms that are activated by statins in cancer cells; some of them are leading to cell death. Statins exert different effects depending on cell line, statin concentration, duration of exposure of cells to statins, and the type of statin being used. It was shown that statins may inhibit the cell cycle by influence on both expression and activity of proteins involved in cell-cycle progression such as cyclins, cyclin-dependent kinases (CDK), and/or inhibitors of CDK. Also, statins may induce apoptosis by both intrinsic and extrinsic pathways. Statin treatment may lead to changes in molecular pathways dependent on the EGF receptor, mainly via inhibition of isoprenoid synthesis. By inhibition of the synthesis of cholesterol, statins may destabilize the cell membrane. Moreover, statins may change the arrangement of transporter OATP1, the localization of HMGCR, and could induce conformational changes in GLUT proteins. In this review, we have tried to gather and compare most of the recent outcomes of the research in this field. We have also attempted to explain why hydrophilic statins are less effective than hydrophobic statins. Finally, we have gathered results from in vivo experiments, presenting the use of statins in combined therapies and discussed a number of molecular targets that could serve as biomarkers predisposing to statin therapy.
TL;DR: The combination of four candidate miRNAs exhibited the highest predictive accuracy in NSCLC screening compared with individual mi RNAs (AUC = 0.97).
Abstract: Lung cancer, predominantly by non-small cell lung cancer (NSCLC), is the leading cause of cancer-related deaths over the world. Late diagnosis is one of important reasons for high mortality rate in lung cancer. Current diagnostic approaches have disadvantages such as low accuracy, high cost, invasive procedure, etc. MicroRNAs were previously proposed as promising novel biomarkers in cancer screening. In this study, we evaluated the predictive power of four candidate miRNAs in NSCLC detection. Our study involved 152 NSCLC patients and 300 healthy controls. Blood samples were obtained from the total 452 subjects. After miRNA extraction from serum, the expression of miRNAs in cases and controls were quantified by qRT-PCR and normalized to the level of U6 small RNA. Statistical analyses were performed to compare miRNA levels between cases and controls. Stratified analyses were employed to compare miRNA levels in NSCLC patients with different clinical characteristics. Serum miR-148a, miR-148b, and miR-152 were significantly downregulated in NSCLC patients. However, overexpression of serum miR-21 was observed in NSCLC patients. The combination of four candidate miRNAs exhibited the highest predictive accuracy in NSCLC screening compared with individual miRNAs (AUC = 0.97). Low level of miRNA-148/152 members may associate with advanced stage, large tumor size, malignant cell differentiation, and metastasis. High expression of miR-21 was possibly correlated with large size tumor and advanced cancer stage. Our results showed the dysregulation of miR-148/152 family and miR-21 in NSCLC patients. Hence, the four candidate miRNAs have great potential to serve as promising novel biomarkers in NSCLC screening. Further large-scale studies are needed to validate our results.
TL;DR: HOTAIR promotes the initiation and chemoresistance of ovarian cancer by activating wnt/β-catenin signaling, suggesting that HOTAIR might be a potent therapeutic target for ovarian cancer treatment.
Abstract: Overexpression of HOTAIR (HOX antisense intergenic RNA) is significantly correlated with tumor progression and poor prognosis in human ovarian cancer. However, the underlying mechanisms are largely unknown. In the present study, we investigated the roles of HOTAIR in the initiation and chemoresistance of ovarian cancer. As our data show, HOTAIR overexpression promoted cell cycle progression (and thus cell proliferation) by activating the wnt/β-catenin signaling pathway. Likewise, knockdown of HOTAIR suppressed cell proliferation and arrested cell cycle at G1 phase via inhibition of wnt/β-catenin signaling. Moreover, the results of primary culture demonstrated that elevated HOTAIR expression correlated positively with chemoresistance in ovarian cancer. In vitro and in vivo, HOTAIR induced cellular resistance to cisplatin by activating the wnt/β-catenin pathway, which could be reversed by pre-treatment with the wnt/β-catenin inhibitor, XAV939. In conclusion, HOTAIR promotes the initiation and chemoresistance of ovarian cancer by activating wnt/β-catenin signaling, suggesting that HOTAIR might be a potent therapeutic target for ovarian cancer treatment.
TL;DR: “Exosomal onco-miRs”, a novel, stable, and noninvasive source for diagnosis and therapy monitoring of esophageal cancer, are identified to be significantly downregulated in adenocarcinoma versus normal and merely or not detectable in exosomes.
Abstract: Diagnostic markers are needed for achieving a cure in esophageal cancer, detecting tumor cells earlier. Exosomes are bioactive vesicles secreted by cells into surrounding body fluids. Exosome formation, cargo content, and delivery have major impact in cancer development. This is the first isolation of exosomes from serum of patients with adenocarcinoma of the esophagus and comparison of exosomal miRNA profiles with matching primary tumor and normal tissues. RNA was extracted for miRNA profiling by real-time TaqMan miR arrays. The miR profiles of exosomal cargo, matching tumor, and normal tissue of a subgroup of adenocarcinoma patients have been compared. “Exosomal onco-miRs” such as miR-223-5p, miR-223-3p, miR-483-5p, miR-409-3p, miR-196b-5p, miR-192-5p, miR-146a-5p, and miR-126-5p have been identified as part of exosomal cargo being overexpressed in corresponding tumor compared to normal. Upregulation of miR-223-5p and miR-483-5p in adenocarcinoma (p = 0.034, p = 0.017) has been verified by an independent cohort of 43 patients with T2-3 adeno- and squamous cell carcinoma. In contrast, miR-224-5p, miR-452-5p, miR-23b-5p, miR-203-5p, miR-1201-5p, miR-149-5p, miR-671-3p, miR-944-5p, miR-27b-3p, and miR-22-3p have been identified to be significantly downregulated in adenocarcinoma versus normal and merely or not detectable in exosomes. “Exosomal onco-miRs” are a novel, stable, and noninvasive source for diagnosis and therapy monitoring of esophageal cancer. Oncogenic shuttle miRNAs present in exosomes may contribute to understanding how tumor cells spread their oncogenic potential to the environment. The “exosomal onco-miRs” identified seem to play a major role and may be applied for noninvasive diagnosis and therapy monitoring of adenocarcinoma of the esophagus.
TL;DR: The results indicate that SREBP1 had important role in tumor progression and appears to be a novel prognostic marker for pancreatic cancer.
Abstract: Sterol regulatory element-binding protein 1 (SREBP1) is a known transcription factor of lipogenic genes, which plays important roles in regulating de novo lipogenesis. Accumulating evidences indicate SREBP1 is involved in tumorigenesis, yet its role in pancreatic cancer remains unclear. Here, we explored the expression characteristic and function of SREBP1 in pancreatic cancer. Analysis of 60 patients with pancreatic ducat cancer showed that SREBP1 level was significantly higher in pancreatic cancer than that in adjacent normal tissues. High expression of SREBP1 predicted poor prognosis in patients with pancreatic cancer. Multivariate analysis revealed that SREBP1 was an independent factor affecting overall survival. SREBP1 silencing resulted in proliferation inhibition and induction of apoptosis in pancreatic cancer cells. Mechanistically, lipogenic genes (acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN), and stearoyl-CoA desaturase-1 (SCD1)) and de novo lipogenesis were promoted by SREBP1. Inhibition of lipogenic genes through specific inhibitors ablated SREBP1-mediated growth regulation. Furthermore, depletion of SREBP1 could suppress lipid metabolism and tumor growth in vivo. Our results indicate that SREBP1 had important role in tumor progression and appears to be a novel prognostic marker for pancreatic cancer.
TL;DR: COL11A1/(pro)collagen 11A1 expression is a remarkable biomarker of human carcinoma-associated stromal cells and carcinoma progression and is correlated with carcinoma aggressiveness and progression, and lymph node metastasis.
Abstract: The COL11A1 human gene codes for the α1 chain of procollagen 11A1 and mature collagen 11A1, an extracellular minor fibrillar collagen. Under regular conditions, this gene and its derived products are mainly expressed by chondrocytes and mesenchymal stem cells as well as osteoblasts. Normal epithelial cells and quiescent fibroblasts from diverse locations do not express them. Mesenchyme-derived tumors and related conditions, such as scleroderma and keloids, are positive for COL11A1/(pro)collagen 11A1 expression, as well as high-grade human gliomas/glioblastomas. This expression is almost absent in benign pathological processes such as breast hyperplasia, sclerosing adenosis, idiopathic pulmonary fibrosis, cirrhosis, pancreatitis, diverticulitis, and inflammatory bowel disease. By contrast, COL11A1/(pro)collagen 11A1 is highly expressed by activated stromal cells of the desmoplastic reaction of different human invasive carcinomas, and this expression is correlated with carcinoma aggressiveness and progression, and lymph node metastasis. COL11A1 upregulation has been shown to be associated to TGF-β1, Wnt, and Hh signaling pathways, which are especially active in cancer-associated stromal cells. At the front of invasive carcinomas, neoplastic epithelial cells, putatively undergoing epithelial-to-mesenchymal transition, and carcinoma-derived cells with highly metastatic capabilities, can express COL11A1. Thus, in established metastases, the expression of COL11A1/(pro)collagen 11A1 could rely on both the metastatic epithelial cells and/or the accompanying activated stromal cells. COL11A1/(pro)collagen 11A1 expression is a remarkable biomarker of human carcinoma-associated stromal cells and carcinoma progression.
TL;DR: The study revealed the oncogenic role of LDHA in prostate cancer and suggested that LDHA might be a potential therapeutic target and decreased Warburg effect were found after LDHA knockdown or FX11 treatment in PC-3 and DU145 cells.
Abstract: A key hallmark of cancer cells is their altered metabolism, known as Warburg effect. Lactate dehydrogenase A (LDHA) executes the final step of aerobic glycolysis and has been reported to be involved in the tumor progression. However, the function of LDHA in prostate cancer has not been studied. In current study, we observed overexpression of LDHA in the clinical prostate cancer samples compared with benign prostate hyperplasia tissues as demonstrated by immunohistochemistry and real-time qPCR. Attenuated expression of LDHA by siRNA or inhibition of LDHA activities by FX11 inhibited cell proliferation, migration, invasion, and promoted cell apoptosis of PC-3 and DU145 cells. Mechanistically, decreased Warburg effect as demonstrated by reduced glucose consumption and lactate secretion and reduced expression of MMP-9, PLAU, and cathepsin B were found after LDHA knockdown or FX11 treatment in PC-3 and DU145 cells. Taken together, our study revealed the oncogenic role of LDHA in prostate cancer and suggested that LDHA might be a potential therapeutic target.
TL;DR: There is evidence which implies folate-conjugated NPs can selectively deliver anti-tumor drugs into cancer cells both in vitro and in vivo, and this review will discuss about the efficiency of different folates in cancer therapy.
Abstract: The selective and efficient drug delivery to tumor cells can remarkably improve different cancer therapeutic approaches. There are several nanoparticles (NPs) which can act as a potent drug carrier for cancer therapy. However, the specific drug delivery to cancer cells is an important issue which should be considered before designing new NPs for in vivo application. It has been shown that cancer cells over-express folate receptor (FR) in order to improve their growth. As normal cells express a significantly lower levels of FR compared to tumor cells, it seems that folate molecules can be used as potent targeting moieties in different nanocarrier-based therapeutic approaches. Moreover, there is evidence which implies folate-conjugated NPs can selectively deliver anti-tumor drugs into cancer cells both in vitro and in vivo. In this review, we will discuss about the efficiency of different folate-conjugated NPs in cancer therapy.
TL;DR: HOTAIR served as an onco-lncRNA in cervical cancer which could enhance various aggressive biological behaviors and it was proved that HOTAIR execute its functions mainly through inhibiting the p21 expression.
Abstract: We previously reported the frequent overexpression of HOX Antisense Intergenic RNA (HOTAIR) in human cervical cancer, which was significantly correlated with tumor progression and poor prognosis. In the present study, we investigated the detailed biological functions of HOTAIR in cervical cancer. In vitro, upregulation of HOTAIR inhibited apoptosis and promoted cellular proliferation, cell cycle progression, migration, and invasion; on the contrast, downregulation of HOTAIR induced more apoptosis, suppressed cellular proliferation, cell cycle, migration, and invasion. Moreover, a high level of HOTAIR was notably associated with radio-resistance and downregulation of p21 in the primary cultured cervical cancer cells. Further, we demonstrated that elevated HOTAIR could induce radio-resistance via inhibiting p21 in HeLa cells, while knockdown of HOTAIR upregulated p21 and consequentially increased the radio-sensitivity of C33A cells. Consistently, stable knockdown of HOTAIR significantly suppressed tumor growth and sensitized cervical cancer to radiotherapy in vivo. In conclusion, HOTAIR served as an onco-lncRNA in cervical cancer which could enhance various aggressive biological behaviors. Moreover, we proved that HOTAIR execute its functions mainly through inhibiting the p21 expression. These results proposed that targeting HOTAIR might be a potent therapeutic strategy in cervical cancer, especially for those patients who accepted radiotherapy.
TL;DR: Subgroup analysis showed PNI was generally a significant prognostic factor in different clinical situations and could assist the identification of patients with poor prognosis and be a hierarchical factor in the future SCLC clinical trials.
Abstract: Recent studies have shown the prognostic nutritional index (PNI) had prognostic value in some solid tumors. However, no studies have examined its prognostic role in small-cell lung cancer (SCLC) patients. In this retrospective study, 724 consecutive SCLC patients were included between 2006 and 2013. Demographic, clinical, and laboratory data were collected. The PNI was calculated as 10 × serum albumin value (g/dl) + 0.005 × peripheral lymphocyte count (per mm3). Univariate and multivariate analyses were performed to assess the prognostic value of relevant factors. The optimal cut-off value of PNI for OS stratification was determined to be 52.48. A total of 464 and 260 patients were assigned to low and high PNI groups, respectively. Compared with low PNI, high PNI was associated with older age, advanced stage, and elevated lactate dehydrogenase (LDH). Median overall survival (OS) was worse in the low PNI group (low vs high, 15.90 vs 25.27 months; HR, 0.62; p < 0.001). In multivariate analysis, stage, performance status, LDH, and PNI were independent prognostic factors for OS. Subgroup analysis showed PNI was generally a significant prognostic factor in different clinical situations. The assessment of PNI could assist the identification of patients with poor prognosis and be a hierarchical factor in the future SCLC clinical trials.
TL;DR: In 20 patients undergoing pancreatic resection, 10 mL blood sample was collected intraoperatively from both systemic circulation and portal vein, and CTCs were found in 45 % of the patients, and no correlation between C TCs and survival was found.
Abstract: Pancreatic cancer patients underwent surgical resection often present distant metastases early after surgery. Detection of circulating tumor cells (CTCs) has been correlated to a worse oncological outcome in patients with advanced pancreatic cancer. The objective of this pilot study is to investigate the possible prognostic role of CTCs in patients undergoing surgery for pancreatic cancer. In 20 patients undergoing pancreatic resection, 10 mL blood sample was collected intraoperatively from both systemic circulation (SC) and portal vein (PV). Blood sample was analyzed for CTCs with CellSearch® system. All patients underwent an oncologic follow-up for at least 3 years, quarterly. CTCs were detected in nine (45 %) patients: five patients had CTCs in PV only, three patients in both SC and PV, and one patient in SC only. CTC-positive and CTC-negative patients were similar for demographics and cancer stage pattern. No significant differences were found in both overall and disease-free survival between CTC-positive and CTC-negative patients. At 3-year follow-up, portal vein CTC-positive patients presented a higher rate of liver metastases than CTC-negative patients (53 vs. 8 %, p = 0.038). CTCs were found in 45 % of the patients. No correlation between CTCs and survival was found. The presence of CTCs in portal vein has been associated to higher rate of liver metastases after surgery.
TL;DR: The results of the current study suggested that serum miR-200c andmiR-141 were able to discriminate the ovarian cancer patients from healthy controls, and may be predictive biomarkers for ovarian cancer prognosis.
Abstract: Ovarian cancer is the fifth leading cause of female death globally due to its low survival rates Thus, improved approaches for ovarian cancer detection are urgently needed MicroRNAs as a new class of biomarkers have been explored in recent studies This study was trying to identify and validate the two kinds of serum microRNA (miR-200c and miR-141) as biomarkers for ovarian cancer We extracted serum samples from 74 epithelial ovarian cancer patients, 19 borderline ovarian cancer, and 50 healthy controls Relative expression of these miRNA markers were measured by quantificational real-time polymerase chain reaction assay (qRT-PCR) Receiver operating characteristics (ROC) and area under the ROC curve (AUC) were used to validate the diagnostic value of miR-200c and miR-141 Kaplan-Meier curve and the log-rank test were conducted to detect the prognostic value of miR-200c and miR-141 miR-200c and miR-141 were significantly elevated in the epithelial ovarian cancer patients compared to healthy controls The relative expression level of miR-200c showed a descending trend from early stages to advanced stages, while the level of miR-141 displayed an escalating trend Patients with high miR-200c level achieved significantly a higher 2-year survival rate compared with the other group (P < 0001), while low miR-141 group showed a significantly higher survival rate The results of the current study suggested that serum miR-200c and miR-141 were able to discriminate the ovarian cancer patients from healthy controls In addition, miR-200c and miR-141 may be predictive biomarkers for ovarian cancer prognosis Further large-scale studies are still needed to confirm our findings
TL;DR: This review summarizes the current understanding of the interplay between ER stress and ROS and discusses how damage-associated molecular patterns (DAMPs) function as modulators of immunogenic cell death and how natural products and drugs have shown potential in regulating ER Stress and ROS in different cancer cell lines.
Abstract: Prior research has demonstrated how the endoplasmic reticulum (ER) functions as a multifunctional organelle and as a well-orchestrated protein-folding unit. It consists of sensors which detect stress-induced unfolded/misfolded proteins and it is the place where protein folding is catalyzed with chaperones. During this folding process, an immaculate disulfide bond formation requires an oxidized environment provided by the ER. Protein folding and the generation of reactive oxygen species (ROS) as a protein oxidative byproduct in ER are crosslinked. An ER stress-induced response also mediates the expression of the apoptosis-associated gene C/EBP-homologous protein (CHOP) and death receptor 5 (DR5). ER stress induces the upregulation of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptor and opening new horizons for therapeutic research. These findings can be used to maximize TRAIL-induced apoptosis in xenografted mice. This review summarizes the current understanding of the interplay between ER stress and ROS. We also discuss how damage-associated molecular patterns (DAMPs) function as modulators of immunogenic cell death and how natural products and drugs have shown potential in regulating ER stress and ROS in different cancer cell lines. Drugs as inducers and inhibitors of ROS modulation may respectively exert inducible and inhibitory effects on ER stress and unfolded protein response (UPR). Reconceptualization of the molecular crosstalk among ROS modulating effectors, ER stress, and DAMPs will lead to advances in anticancer therapy.
TL;DR: It is shown that inflammasome components were markedly upregulated in lung cancer and elicited the maturation of IL-1β and IL-18, and pharmacotherapeutics targetinginflammasomes might be novel adjuvant therapy strategies for lung cancer.
Abstract: As pivotal elements involved in inflammation, inflammasomes represent a group of multiprotein complexes triggering the maturation of proinflammatory cytokine interleukin (IL)-1β and IL-18. Although the importance of the inflammasomes in inflammatory diseases is well appreciated, a precise characterization of their expressions in lung cancer remains obscure. This study aimed to determine the expressions of inflammasomes in various lung cancer cell lines and tissues to understand their potential roles in lung cancer. Our findings showed that inflammasome components were markedly upregulated in lung cancer and elicited the maturation of IL-1β and IL-18. In addition, enormous variations in subtypes and levels of inflammasomes were detected in lung cancers depending on their histological type and grading, invasion ability, as well as chemoresistance. Generally, AIM2 inflammasome was overexpressed in nonsmall cell lung cancer (NSCLC), while NLRP3 inflammasome was upregulated in lung adenocarcinoma (ADC) and small cell lung cancer (SCLC). The high-metastatic or cisplatin-sensitive NSCLC cells expressed more inflammasome components and products than their counterpart low-metastatic or cisplatin-resistant NSCLC cells, respectively. In resected lung cancer tissues, high-grade ADC expressed more inflammasome components and products than low-grade ADC. Together, these findings suggest that inflammasomes may be crucial biomarkers for lung cancer as well as potential modulators of the biological behaviors of lung cancer. Further, pharmacotherapeutics targeting inflammasomes might be novel adjuvant therapy strategies for lung cancer.
TL;DR: High expression of PCAT-1 was specifically correlated with invasion of cancer tissues, metastasis of lymph node, and advanced tumor stage of ESCC, indicating a potential diagnostic target in ESCC patients.
Abstract: Recent studies reveal that long noncoding RNAs (lncRNAs) play critical regulatory roles in cancer biology. Prostate cancer-associated ncRNA transcript 1 (PCAT-1) is one of the lncRNAs involved in cell apoptosis and proliferation of prostate cancer. This study aimed to assess the potential role of PCAT-1 specifically in the pathogenesis of esophageal squamous cell carcinoma (ESCC). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression level of PCAT-1 in matched cancerous tissues and adjacent noncancerous tissues from 130 patients with ESCC, 34 patients with non-small cell lung cancer (NSCLC), and 30 patients with gastric carcinoma (GC). The correlation of PCAT-1 with clinicopathological features and prognosis were also analyzed. The expression of PCAT-1 was significantly higher in human ESCC compared with the adjacent noncancerous tissues (70.8 %, p < 0.01), and the high level of PCAT-1 expression was significantly correlated with invasion of the tumor (p = 0.024), advanced clinical stage (p = 0.003), lymph node metastasis (p = 0.032), and poor prognosis. However, PCAT-1 mRNA expression had no significant difference between paired primary cancerous tissues and the adjacent noncancerous tissues in 34 cases of NSCLC (p = 0.293) and 30 cases of GC (p = 0.125). High expression of PCAT-1 was specifically correlated with invasion of cancer tissues, metastasis of lymph node, and advanced tumor stage of ESCC. High expression of PCAT-1 might reflect poor prognosis of ESCC and indicate a potential diagnostic target in ESCC patients. Adjuvant therapy targeting PCAT-1 molecule might be effective in treatment of ESCC.
TL;DR: HOTAIR is a direct target of HIF-1α through interaction with putative HREs in the upstream region of HOTAIR in NSCLC cells and was upregulated by hypoxia in NSClC cells, suggesting that suppression of HotaIR upon hypoxial conditions could be a novel therapeutic strategy.
Abstract: Despite the fact that great advances have been made in the management of non-small cell lung cancer (NSCLC), the prognosis of advanced NSCLC remains very poor. HOX transcript antisense intergenic RNA (HOTAIR) has been identified as an oncogenic long noncoding RNA (lncRNA) that is involved in the progression of a variety of carcinomas and acts as a negative prognostic biomarker. Yet, little is known about the effect of HOTAIR in the hypoxic microenvironment of NSCLC. The expression and promoter activity of HOTAIR were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and luciferase reporter assay. The function of the hypoxia-inducible factor-1α (HIF-1α) binding site to hypoxia-responsive elements (HREs) in the HOTAIR promoter region was tested by luciferase reporter assay with nucleotide substitutions. The binding of HIF-1α to the HOTAIR promoter in vivo was confirmed by chromatin immunoprecipitation assay (CHIP) and electrophoretic mobility shift assay (EMSA). The effect of HIF-1α suppression by small interference RNA or YC-1 on HOTAIR expression was also determined. In the present study, we demonstrated that HOTAIR was upregulated by hypoxia in NSCLC cells. HOTAIR is a direct target of HIF-1α through interaction with putative HREs in the upstream region of HOTAIR in NSCLC cells. Furthermore, HIF-1α knockdown or inhibition could prevent HOTAIR upregulation under hypoxic conditions. Under hypoxic conditions, HOTAIR enhanced cancer cell proliferation, migration, and invasion. These data suggested that suppression of HOTAIR upon hypoxia of NSCLC could be a novel therapeutic strategy.
TL;DR: It is suggested that miR-21 acts as a molecular switch to regulate aerobic glycolysis in bladder cancer cells via the PTEN/phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway.
Abstract: Cancer cells exhibit the ability to metabolise glucose to lactate even under aerobic conditions for energy. This phenomenon is known as the Warburg effect and can be a potential target to kill cancer cells. Several studies have shown evidence for interplay between microRNAs and key metabolic enzyme effecters, which can facilitate the Warburg effect in cancer cells. In the present study, a microRNA sponge forcibly expressed using a lentiviral vector was utilised to knock down miR-21 expression in vitro. qPCR and Western blot assays were performed to evaluate the expression of a regulatory factor related to aerobic glycolysis and the signalling pathway it regulates. In bladder cancer specimens, expression levels of glycolysis-related genes [glucose transporter (GLUT)1, GLUT3, lactic dehydrogenase (LDH)A, LDHB, hexokinase (HK)1, HK2, pyruvate kinase type M (PKM) and hypoxia-inducible factor 1-alpha (HIF-1α)] were higher in tumour tissues than in adjacent tissues, suggesting the role of glycolysis in bladder cancer. miR-21 inhibition in bladder cancer cell lines resulted in reduction in tumour aerobic glycolysis. Decrease in glucose uptake and lactate production was observed upon expression of the miR-21 sponge, which promoted phosphatase and tensin homologue (PTEN) expression, decreased phosphorylated AKT and deactivated mTOR. Furthermore, messenger RNA (mRNA) and protein expression levels of glycolysis-related genes were also lower in miR-21 sponge cells compared to miR-21 control cells. Our findings suggest that miR-21 acts as a molecular switch to regulate aerobic glycolysis in bladder cancer cells via the PTEN/phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway. Blocking miR-21 function can be an effective diagnostic and therapeutic approach either by itself or in combination with existing methods to treat bladder cancer.
TL;DR: In this article, the role of BRAF-activated non-coding RNA (BANCR) in the proliferation and metastasis in malignant melanoma and lung cancer was explored.
Abstract: Recent evidence shows that BRAF-activated non-coding RNA (BANCR) acts as a critical role in the proliferation and metastasis in malignant melanoma and lung cancer; however, little is known about the significance of lncRNA BANCR in retinoblastoma. The purpose of our study is to explore the role of lncRNA BANCR in retinoblastoma clinical samples and cell lines. The expression of lncRNA BANCR was measured in 60 retinoblastoma samples and normal retina samples by using RT-PCR. The effects of lncRNA BANCR on cell proliferation, migration, and invasion were also explored. In our results, lncRNA BANCR is overexpressed in retinoblastoma tissues and cell lines and is associated with tumor size, choroidal invasion, and optic nerve invasion. Moreover, patients with high levels of lncRNA BANCR expression had poorer survival than those with lower levels of lncRNA BANCR expression. Multivariate analysis showed that increased lncRNA BANCR expression was a poor independent prognostic factor for retinoblastoma patients. Furthermore, knocking down lncRNA BANCR expression significantly suppressed the retinoblastoma cell proliferation, migration, and invasion in vitro. In conclusion, lncRNA BANCR plays a significant role in retinoblastoma aggressiveness and prognosis and may act as a promising target for therapeutic strategy and prognostic prediction.
TL;DR: A comprehensive comparison of three methods currently being used for V600E detection in clinical samples concluded that the VE1 antibody is not recommendable for clinical tests of colorectal cancer samples and may be useful as a screening tool guiding further analytical approaches.
Abstract: Personalized cancer care requires reliable biomarkers. While the BRAF V600E mutation is implemented in the clinic, no method for its detection has so far been established as reference. We aimed to perform a comprehensive comparison of three methods currently being used for V600E detection in clinical samples. We analysed genomic DNA from 127 malignant melanomas (77 patients) and 389 tumours from 141 colorectal cancer patients (383 liver metastases and 6 primary tumours) by Sanger sequencing and a single probe-based high-resolution melting assay (LightMix). Formalin-fixed paraffin-embedded (FFPE) tissue from a subset of these lesions (n = 77 and 304, respectively) was analysed by immunohistochemistry (IHC) using the V600E-specific antibody VE1. In a dilution series of V600E-mutated DNA in wild-type DNA, the detection limit for the LightMix assay was 1:1000 mutated alleles while it was 1:10 for Sanger sequencing. In line with this, we detected 15 additional mutated melanoma samples and two additional mutated metastatic colorectal cancer samples by the LightMix assay compared to Sanger sequencing. For the melanoma samples, we observed high concordance between DNA-based methods and analysis by IHC. However, in colorectal samples, IHC performed poorly with 12 samples being scored as V600E positive exclusively by IHC and nine samples being scored as V600E negative exclusively by IHC. In conclusion, the VE1 antibody is not recommendable for clinical tests of colorectal cancer samples. For melanoma samples, IHC may be useful as a screening tool guiding further analytical approaches.