Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gain of chromosome 5p is seen in over 50% of advanced cervical squamous cell carcinomas (SCCs), although the genes responsible for the selective advantage provided by this abnormality are poorly understood. In the W12 cervical carcinogenesis model, we observed that 5p gain was rapidly selected over approximately 15 population doublings and was associated with the acquisition of a growth advantage and invasiveness. The most significantly upregulated transcript following 5p gain was the microRNA (miRNA) processor Drosha. In clinically progressed cervical SCC, Drosha copy-number gain was seen in 21/36 clinical samples and 8/10 cell lines and there was a significant association between Drosha transcript levels and copy-number gain. Other genes in the miRNA processing pathway, DGCR8, XPO5 and Dicer, showed infrequent copy-number gain and over-expression. Drosha copy-number and expression were not elevated in pre-malignant cervical squamous intraepithelial lesions. Importantly, global miRNA profiling showed that Drosha over-expression in cervical SCC appears to be of functional significance. Unsupervised principal component analysis of a mixed panel of cervical SCC cell lines and clinical specimens showed clear separation according to Drosha over-expression. miRNAs most significantly associated with Drosha over-expression are implicated in carcinogenesis in other tissues, suggesting that they regulate fundamental processes in neoplastic progression. Our evidence suggests that copy-number driven over-expression of Drosha and consequent changes in miRNAs are likely to be important contributors to the selective advantage provided by 5p gain in cervical neoplastic progression.
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PMID:Global microRNA profiles in cervical squamous cell carcinoma depend on Drosha expression levels. 1747 71

MicroRNAs (miR) are small noncoding RNAs that are predicted to regulate up to 30% of protein-encoding genes. miR maturation requires functional microRNA machinery, including the Dicer protein. We review our experience with mucoepidermoid carcinoma (MEC) and characterize the prognostic value of Dicer expression. Expression of Dicer was assessed in 78 MEC by immunohistochemistry. Dicer expression was scored semiquantitatively and relative to the internal controls: large excretory/striated ducts or basal/parabasal layers of normal squamous epithelium (mucosa). Dicer scores were then correlated with clinical and pathologic parameters. Dicer over- and/or under-expression were more commonly seen in high-grade MEC (83%) than in low/intermediate grade MEC (35%; p=0.002) and in stage III/IV MEC (80%) than in stage I/II MEC (41%; p=0.04). Abnormal Dicer expression correlates with high-grade and advanced stage, acting as a univariate predictor of poor disease-specific survival (DSS) in MEC. Age and stage were independent predictors of poor DSS on multivariate analysis. Abnormal immunoexpression of Dicer in aggressive MEC suggests a role for miR and miR machinery in tumor progression.
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PMID:Mucoepidermoid carcinoma of upper aerodigestive tract: clinicopathologic study of 78 cases with immunohistochemical analysis of Dicer expression. 1823 38

SOX4 is a critical developmental transcription factor in vertebrates and is required for precise differentiation and proliferation in multiple tissues. In addition, SOX4 is overexpressed in many human malignancies, but the exact role of SOX4 in cancer progression is not well understood. Here, we have identified the direct transcriptional targets of SOX4 using a combination of genome-wide localization chromatin immunoprecipitation-chip analysis and transient overexpression followed by expression profiling in a prostate cancer model cell line. We have also used protein-binding microarrays to derive a novel SOX4-specific position-weight matrix and determined that SOX4 binding sites are enriched in SOX4-bound promoter regions. Direct transcriptional targets of SOX4 include several key cellular regulators, such as EGFR, HSP70, Tenascin C, Frizzled-5, Patched-1, and Delta-like 1. We also show that SOX4 targets 23 transcription factors, such as MLL, FOXA1, ZNF281, and NKX3-1. In addition, SOX4 directly regulates expression of three components of the RNA-induced silencing complex, namely Dicer, Argonaute 1, and RNA Helicase A. These data provide new insights into how SOX4 affects developmental signaling pathways and how these changes may influence cancer progression via regulation of gene networks involved in microRNA processing, transcriptional regulation, the TGFbeta, Wnt, Hedgehog, and Notch pathways, growth factor signaling, and tumor metastasis.
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PMID:Genome-wide promoter analysis of the SOX4 transcriptional network in prostate cancer cells. 1914 88

Global mature microRNA (miRNA) expression is downregulated in cancers, and impaired miRNA processing enhances cancer cell proliferation. These findings indicate that the miRNA system generally serves as a negative regulator during cancer progression. In this study, we investigated the role of the miRNA system in cancer cell invasion by determining the effect of damaging miRNA processing on invasion-essential urokinase-type plasminogen activator (uPA) expression in breast cancer cells. Short hairpin RNAs specific for Drosha, DGCR8, and Dicer, key components of miRNA processing machinery, were introduced into 2 breast cancer cell lines with high uPA expression and 2 lines with poor uPA expression. Knockdown of Drosha, DGCR8, or Dicer led to even higher uPA expression in cells with high uPA expression, while it was unable to increase uPA level in cells with poor uPA expression, suggesting that the miRNA system most likely impacts uPA expression as a facilitator. In cells with high uPA expression, knockdown of Drosha, DGCR8, or Dicer substantially increased in vitro invasion, and depleting uPA abrogated enhanced invasion. These results thus link the augmented invasion conferred by impaired miRNA processing to upregulated uPA expression. uPA mRNA was a direct target of miR-193a/b and miR-181a, and a higher uPA level in cells with impaired miRNA processing resulted from less mature miR-193a/b and miR-181a processed from their respective primary miRNAs. Importantly, the levels of mature miR-193a, miR-193b, and miR-181a, but not their respective primary miRNAs, were lower in high uPA-expressing cells compared to cells with low uPA expression, and this apparently attributed to lower Drosha/DGCR8 expression in high uPA-expressing cells. This study suggests that less efficient miRNA processing can be a mechanism responsible for reduced levels of mature forms of tumor-suppressive miRNAs frequently detected in cancers.
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PMID:Impaired MicroRNA Processing Facilitates Breast Cancer Cell Invasion by Upregulating Urokinase-Type Plasminogen Activator Expression. 2177 87

MET, a receptor protein tyrosine kinase activated by hepatocyte growth factor (HGF), is a crucial determinant of metastatic progression. Recently, we have identified p53 as an important regulator of MET-dependent cell motility and invasion. This regulation occurs via feedforward loop suppressing MET expression by miR-34-dependent and -independent mechanisms. Here, by using Dicer conditional knockout, we provide further evidence for microRNA-independent MET regulation by p53. Furthermore, we show that while MET levels increase immediately after p53 inactivation, mutant cells do not contain active phosphorylated MET and remain non-invasive for a long latency period at contrary to cell culture observations. Evaluation of mouse models of ovarian and prostate carcinogenesis indicates that formation of desmoplastic stroma, associated production of HGF by stromal cells and coinciding MET phosphorylation precede cancer invasion. Thus, initiation mutation of p53 is sufficient for preprogramming motile and invasive properties of epithelial cells, but the stromal reaction may represent a critical step for their manifestation during cancer progression.
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PMID:MET-dependent cancer invasion may be preprogrammed by early alterations of p53-regulated feedforward loop and triggered by stromal cell-derived HGF. 2207 25

MicroRNAs are posttranscriptional regulators of messenger RNA synthesis that are intracellularly processed and transferred by the microRNA-regulating machinery consisting of Drosha, Dicer, and Argonaute. The present study analyzed the expression and clinical role of the microRNA-regulating machinery in advanced-stage ovarian carcinoma. Drosha, Dicer, Argonaute 1, and Argonaute 2 messenger RNA levels were analyzed in 144 specimens (82 effusions, 33 primary carcinomas, and 29 solid metastases) using quantitative polymerase chain reaction. Dicer, Argonaute 1, and Argonaute 2 protein levels were analyzed in 103 of the above specimens by Western blotting. Argonaute 1, Argonaute 2, and Drosha messenger RNAs were overexpressed in effusions compared with primary carcinomas and solid metastases (P<.001), whereas Argonaute 1 protein expression was highest in solid metastases (P=.004). Significantly higher expression of all 4 messenger RNAs was found in effusions compared with primary carcinomas (P<.001 to P=.006), whereas Argonaute 2 messenger RNA (P=.002), Drosha messenger RNA (P=.009), and Dicer protein (P=.006) were overexpressed in solid metastases compared with primary carcinomas. Drosha, Dicer, Argonaute 1, and Argonaute 2 messenger RNAs and protein levels in effusions were unrelated to clinicopathologic parameters. In primary carcinomas, higher levels of 3 messenger RNAs were significantly associated with high-grade histology (P=.003 for Dicer and P=.01 for Drosha and Argonaute 1). Higher Argonaute 2 messenger RNA levels in prechemotherapy effusions were related to shorter progression-free survival (P=.049), a finding that retained its significance in multivariate Cox analysis (P=.046). In conclusion, Drosha, Dicer, Argonaute 1, and Argonaute 2 are differentially expressed at different metastatic sites in ovarian carcinoma compared with primary carcinomas, suggesting a role for these molecules in tumor progression. Their clinical role in metastatic ovarian carcinoma merits further research.
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PMID:Argonaute, Dicer, and Drosha are up-regulated along tumor progression in serous ovarian carcinoma. 2264 51

microRNAs (miRNAs) are aberrantly expressed in cancer. An enzyme essential for miRNA processing is Dicer, whose expression is deregulated in diverse types of cancer and correlates with tumor progression. However, whether the regulation of Dicer expression affects tongue squamous cell carcinoma is unknown. In the present study, we investigated how silencing the expression of Dicer alters cell proliferation, cell cycle patterns, and cell migration and invasion in the Tca-8113 tongue squamous cell carcinoma cell line. Dicer expression levels were determined using quantitative PCR and western blot analysis in normal oral gingival epithelial cells and in two tongue squamous cell carcinoma lines, Tca-8113 and UM-1. Tca-8113 cells were transfected with Dicer siRNA or a negative control siRNA. Cell proliferation was determined using the MTT assay and the cell cycle was examined using flow cytometry. Cell migration and invasion changes were evaluated using wound-healing, adherence and Transwell assays. Dicer was expressed at lower levels in the tongue squamous cell carcinoma cell lines Tca-8113 and UM-1 compared to normal gingival epithelial cells, and less Dicer was expressed in UM-1 cells compared to Tca-8113 cells. Notably, Tca-8113 cells transfected with Dicer siRNA had significantly higher proliferative and invasive abilities than cells transfected with the negative control siRNA or non-transfected cells. Silencing Dicer may promote the progression of tongue squamous cell carcinoma. Dicer could serve a promising biomarker and a potential therapeutic target for tongue squamous cell carcinoma.
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PMID:Silencing Dicer expression enhances cellular proliferative and invasive capacities in human tongue squamous cell carcinoma. 2431 82

Hallmarks of cancer are fundamental principles involved in cancer progression. We propose an additional generalized hallmark of malignant transformation corresponding to the differential expression of a family of mitochondrial ncRNAs (ncmtRNAs) that comprises sense and antisense members, all of which contain stem-loop structures. Normal proliferating cells express sense (SncmtRNA) and antisense (ASncmtRNA) transcripts. In contrast, the ASncmtRNAs are down-regulated in tumor cells regardless of tissue of origin. Here we show that knockdown of the low copy number of the ASncmtRNAs in several tumor cell lines induces cell death by apoptosis without affecting the viability of normal cells. In addition, knockdown of ASncmtRNAs potentiates apoptotic cell death by inhibiting survivin expression, a member of the inhibitor of apoptosis (IAP) family. Down-regulation of survivin is at the translational level and is probably mediated by microRNAs generated by dicing of the double-stranded stem of the ASncmtRNAs, as suggested by evidence presented here, in which the ASncmtRNAs are bound to Dicer and knockdown of the ASncmtRNAs reduces reporter luciferase activity in a vector carrying the 3'-UTR of survivin mRNA. Taken together, down-regulation of the ASncmtRNAs constitutes a vulnerability or Achilles' heel of cancer cells, suggesting that the ASncmtRNAs are promising targets for cancer therapy.
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PMID:Down-regulation of the antisense mitochondrial non-coding RNAs (ncRNAs) is a unique vulnerability of cancer cells and a potential target for cancer therapy. 2510 Jul 22

Growing evidence suggests that breast cancer cell plasticity arises due to a partial reactivation of epithelial-mesenchymal transition (EMT) programs in order to give cells pluripotency, leading to a stemness-like phenotype. A complete EMT would be a dead end program that would render cells unable to fully metastasize to distant organs. Evoking the EMT-mesenchymal-to-epithelial transition (MET) cascade promotes successful colonization of distal target tissues. It is unlikely that direct reprogramming or trans-differentiation without passing through a pluripotent stage would be the preferred mechanism during tumor progression. This review focuses on key EMT transcriptional regulators, EMT-transcription factors involved in EMT (TFs) and the miRNA pathway, which are deregulated in breast cancer, and discusses their implications in cancer cell plasticity. Cross-regulation between EMT-TFs and miRNAs, where miRNAs act as co-repressors or co-activators, appears to be a pivotal mechanism for breast cancer cells to acquire a stem cell-like state, which is implicated both in breast metastases and tumor recurrence. As a master regulator of miRNA biogenesis, the ribonuclease type III endonuclease Dicer plays a central role in EMT-TFs/miRNAs regulating networks. All these EMT-MET key regulators represent valuable new prognostic and predictive markers for breast cancer as well as promising new targets for drug-resistant breast cancers.
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PMID:Epithelial-mesenchymal transition transcription factors and miRNAs: "Plastic surgeons" of breast cancer. 2511 47

Metastasis of solid tumors is associated with poor prognosis and bleak survival rates. Tumor-infiltrating myeloid cells (TIMs) are known to promote metastasis, but the mechanisms underlying their collaboration with tumor cells remain unknown. Here, we report an oncogenic role for microRNA (miR) in driving M2 reprogramming in TIMs, characterized by the acquisition of pro-tumor and pro-angiogenic properties. The expression of miR-21, miR-29a, miR-142-3p and miR-223 increased in myeloid cells during tumor progression in mouse models of breast cancer and melanoma metastasis. Further, we show that these miRs are regulated by the CSF1-ETS2 pathway in macrophages. A loss-of-function approach utilizing selective depletion of the miR-processing enzyme Dicer in mature myeloid cells blocks angiogenesis and metastatic tumor growth. Ectopic expression of miR-21 and miR-29a promotes angiogenesis and tumor cell proliferation through the downregulation of anti-angiogenic genes such as Col4a2, Spry1 and Timp3, whereas knockdown of the miRs impedes these processes. miR-21 and miR-29a are expressed in Csf1r+ myeloid cells associated with human metastatic breast cancer, and levels of these miRs in CD115+ non-classical monocytes correlates with metastatic tumor burden in patients. Taken together, our results suggest that miR-21 and miR-29a are essential for the pro-tumor functions of myeloid cells and the CSF1-ETS2 pathway upstream of the miRs serves as an attractive therapeutic target for the inhibition of M2 remodeling of macrophages during malignancy. In addition, miR-21 and miR-29a in circulating myeloid cells may potentially serve as biomarkers to measure therapeutic efficacy of targeted therapies for CSF1 signaling.
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PMID:CSF1-ETS2-induced microRNA in myeloid cells promote metastatic tumor growth. 2524 94


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