UMLS:C0178874 - FACTA Search

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Query: UMLS:C0178874 (tumor progression)
40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

N-myc downstream regulated gene-1 (NDRG1) is a potent metastasis suppressor that is regulated by hypoxia, metal ions including iron, the free radical nitric oxide (NO^.), and various stress stimuli. This intriguing molecule exhibits diverse functions in cancer, inhibiting epithelial-mesenchymal transition (EMT), cell migration and angiogenesis by modulation of a plethora of oncogenes via cellular signaling. Thus, pharmacological targeting of NDRG1 signaling in cancer is a promising therapeutic strategy. Of note, novel anti-tumor agents of the di-2-pyridylketone thiosemicarbazone series, which exert the "double punch" mechanism by binding metal ions to form redox-active complexes, have been demonstrated to markedly up-regulate NDRG1 expression in cancer cells. This review describes the mechanisms underlying NDRG1 modulation by the thiosemicarbazones and the diverse effects NDRG1 exerts in cancer. As a major induction mechanism, iron depletion appears critical, with NO^. also inducing NDRG1 through its ability to bind iron and generate dinitrosyl-dithiol iron complexes, which are then effluxed from cells. Apart from its potent anti-metastatic role, several studies have reported a pro-oncogenic role of NDRG1 in a number of cancer-types. Hence, it has been suggested that NDRG1 plays pleiotropic roles depending on the cancer-type. The molecular mechanism(s) underlying NDRG1 pleiotropy remain elusive, but are linked to differential regulation of WNT signaling and potentially differential interaction with the tumor suppressor, PTEN. This review discusses NDRG1 induction mechanisms by metal ions and NO^. and both the anti- and possible pro-oncogenic functions of NDRG1 in multiple cancer-types and compares the opposite effects this protein exerts on cancer progression.
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PMID:Pharmacological targeting and the diverse functions of the metastasis suppressor, NDRG1, in cancer. 3113 12

Background: Metastasis suppressor 1 (MTSS1), a potential metastasis suppressor gene associated with tumor progression, may play an important role in cancer development. Our previous study demonstrated that MTSS1 was downregulated significantly when gastric cancer (GC) progressed and metastasized, suggesting that MTSS1 may be involved in the physiopathologic mechanism of GC. Purpose: The objective of this study was to evaluate the effect of MTSS1 expression on the biological behavior of gastric cancer cell both in vitro and in vivo. Materials and methods: The gain-and-loss function of MTSS1 in GC cells were analyzed after transfection with pEGFP-N1-MTSS1 and ShRNA431. Proliferation and invasion abilities were measured by means of plate clone formation assay and transwell assay. To further explore the underlying mechanism of MTSS1-induced tumor restrain, cell cycle distribution was analyzed using flow cytometry. Results: The results revealed that overexpression of MTSS1 significantly reduced proliferation, migration and invasion of GC cells in vivo and in vitro, while downregulation of MTSS1 had the opposite biological manifestations. Moreover, overexpression of MTSS1 induced accumulation of GC cells in G2/M phase, increased phosphorylated Cdc2 expression and decreased Cdc25C and cyclinB1 levels, suggesting MTSS1 could cause G2/M cell cycle arrest. Conclusion: Our data provided insight into an important role for MTSS1 in suppressing tumor cell proliferation, invasion and migration, indicating that MTSS, as a functional tumor suppressor in GC, could be a potential therapeutic target to prevent GC metastasis.
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PMID:MTSS1 inhibits metastatic potential and induces G2/M phase cell cycle arrest in gastric cancer. 3130 67

The Awd (abnormal wing discs) gene is the Drosophila homolog of human NME1 and NME2 metastasis suppressor genes. These genes play a key role in tumor progression. Extensive studies revealed that intracellular NME1/2 protein levels could be related to either favorable or poor prognosis depending on tissue context. More recently, extracellular activities of NME1/2 proteins have also been reported, including a tumor- promoting function. We used Drosophila as a genetic model to investigate the mechanism controlling intra- and extracellular levels of NME1/2. We examined the role of several components of the ESCRT (endosomal sorting complex required for transport) complex in controlling Awd trafficking. We show that the Vps28 component of the ESCRT-I complex is required for maintenance of normal intracellular level of Awd in larval adipocytes. We already showed that blocking of Shibire (Shi)/Dynamin function strongly- lowers Awd intracellular level. To further investigate this down regulative effect, we analyzed the distribution of endosomal markers in wild type and Shi-defective adipocytes. Our results suggest that Awd does not enter CD63-positive endosomes. Interestingly, we found that in fat body cells, Awd partly- colocalizes with the ESCRT accessory component ALiX, the ALG-2 (apoptosis-linked gene 2)-interacting protein X. Moreover, we show that the intracellular levels of both proteins are downregulated by blocking the function of the Dynamin encoded by the shibire gene.
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PMID:Vps28 Is Involved in the Intracellular Trafficking of Awd, the Drosophila Homolog of NME1/2. 3142 86

Tumor suppressors are cellular proteins typically expressed in normal (non-cancer) cells that not only regulate such cellular functions as proliferation, migration and adhesion, but can also be secreted into extracellular space and serve as biomarkers for pathological conditions or tumor progression. KISS1, a precursor for several shorter peptides, known as metastin (Kisspeptin-54), Kisspeptin-14, Kisspeptin-13 and Kisspeptin-10, is one of those metastasis suppressor proteins, whose expression is commonly downregulated in the metastatic tumors of various origins. The commonly accepted role of KISS1 in metastatic tumor progression mechanism is the ability of this protein to suppress colonization of disseminated cancer cells in distant organs critical for the formation of the secondary tumor foci. Besides, recent evidence suggests involvement of KISS1 in the mechanisms of tumor angiogenesis, autophagy and apoptosis regulation, suggesting a possible role in both restricting and promoting cancer cell invasion. Here, we discuss the role of KISS1 in regulating metastases, the link between KISS1 expression and the autophagy-related biology of cancer cells and the perspectives of using KISS1 as a potential diagnostic marker for cancer progression as well as a new anti-cancer therapeutics.
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PMID:KISS1 in breast cancer progression and autophagy. 3170 28

KISS1, a metastasis suppressor gene, has been shown to block metastasis without affecting primary tumor formation. Loss of KISS1 leads to invasion and metastasis in multiple cancers, which is the leading cause of cancer morbidity and mortality. The discovery of KISS1 has provided a ray of hope for early clinical diagnosis and for designing effective treatments targeting metastatic cancer. However, this goal requires greater holistic understanding of its mechanism of action. In this review, we go back into history and highlight some key developments, from the discovery of KISS1 to its role in regulating multiple physiological processes including cancer. We discuss key emerging roles for KISS1, specifically interactions with tissue microenvironment to promote dormancy and regulation of tumor cell metabolism, acknowledged as some of the key players in tumor progression and metastasis. We finally discuss strategies whereby KISS1 might be exploited clinically to treat metastasis.
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PMID:Role of the tumor microenvironment in regulating the anti-metastatic effect of KISS1. 3208 27

Genetic alterations can drive carcinogenesis. Numerous studies have shown that gene fusion is associated with cancer progression and could provide valuable biomarkers for clinical diagnosis or targets for cancer therapy. Adenoid cystic carcinoma (ACC) is a rare form of adenocarcinoma, characterized by frequent local recurrence and high rates of distant metastasis, ultimately resulting in low survival rates. Owing to the lack of effective therapeutic targets and limited biomarkers for diagnosis, a deeper understanding of the molecular basis of ACC is urgently needed. Here, we show that gene fusion is associated with ACC metastasis. We identified a metastasis suppressor KISS1 fused with a close-by gene, GOLT1A, in highly metastatic ACC cell lines and human specimens. Such fusion blocks KISS1 translation, but not transcription, by introducing 5' upstream open reading frames (uORFs) in the GOLT1A-KISS1 fusion transcript. Deletion of these uORFs rescued KISS1 expression and reduced invasion and migration of metastatic ACC cells. We also detected GOLT1A-KISS1 fusion transcripts in other types of highly metastatic cancer cell lines. Taken together, our results highlight the significance of this novel GOLT1A-KISS1 gene fusion in tumor metastasis and provide a valuable biomarker for clinical diagnosis and future therapeutic targeting of ACC.
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PMID:GOLT1A-KISS1 fusion is associated with metastasis in adenoid cystic carcinomas. 3219 69

MicroRNA (miRNA) dysregulation in cancer causes changes in gene expression programs regulating tumor progression and metastasis. Candidate metastasis suppressor miRNA are often identified by differential expression in primary tumors compared to metastases. Here, we performed comprehensive analysis of miRNA expression in The Cancer Genome Atlas (TCGA) skin cutaneous melanoma (SKCM) tumors (97 primary, 350 metastatic), and identified candidate metastasis-suppressor miRNAs. Differential expression analysis revealed miRNA significantly downregulated in metastatic tumors, including miR-205, miR-203, miR-200a-c, and miR-141. Furthermore, sequential feature selection and classification analysis identified miR-205 and miR-203 as the miRNA best able to discriminate between primary and metastatic tumors. However, cell-type enrichment analysis revealed that gene expression signatures for epithelial cells, including keratinocytes and sebocytes, were present in primary tumors and significantly correlated with expression of the candidate metastasis-suppressor miRNA. Examination of miRNA expression in cell lines revealed that candidate metastasis-suppressor miRNA identified in the SKCM tumors, were largely absent in melanoma cells or melanocytes, and highly restricted to keratinocytes and other epithelial cell types. Indeed, the differences in stromal cell composition between primary and metastatic tumor tissues is the main basis for identification of differential miRNA that were previously classified as metastasis-suppressor miRNAs. We conclude that future studies must consider tumor-intrinsic and stromal sources of miRNA in their workflow to identify bone fide metastasis-suppressor miRNA in cutaneous melanoma and other cancers.
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PMID:Distinguishing Tumor and Stromal Sources of MicroRNAs Linked to Metastasis in Cutaneous Melanoma. 3247 65

The loss of cancer-cell junctions and escape from the primary-tumor microenvironment are hallmarks of metastasis. A tight-junction protein, Claudin 1 (CLDN1), is a metastasis suppressor in lung adenocarcinoma. However, as a metastasis suppressor, the underlying molecular mechanisms of CLDN1 has not been well studied. Methods: The signaling pathway regulated by CLDN1 was analyzed by Metacore software and validated by immunoblots. The effect of the CLDN1-EPHB6-ERK-SLUG axis on the formation of cancer stem-like cells, drug resistance and metastasis were evaluated by sphere assay, aldefluor assay, flow cytometry, migration assay, cytotoxicity, soft agar assay, immunoprecipitation assay and xenograft experiments. Furthermore, the methylation-specific PCR, pyrosequencing assay, chromatin immunoprecipitation and reporter assay were used to study the epigenetic and RUNX3-mediated CLDN1 transcription. Finally, the molecular signatures of RUNX3/CLDN1/SLUG were used to evaluate the correlation with overall survival by using gene expression omnibus (GEO) data. Results: We demonstrated that CLDN1 repressed cancer progression via a feedback loop of the CLDN1-EPHB6-ERK1/2-SLUG axis, which repressed metastasis, drug resistance, and cancer stemness, indicating that CLDN1 acts as a metastasis suppressor. CLDN1 upregulated the cellular level of EPHB6 and enhanced its activation, resulting in suppression of ERK1/2 signaling. Interestingly, DNA hypermethylation of the CLDN1 promoter abrogated SLUG-mediated suppression of CLDN1 in low-metastatic cancer cells. In contrast, the histone deacetylase inhibitor trichostatin A or vorinostat facilitated CLDN1 expression in high-metastatic cancer cells and thus increased the efficacy of chemotherapy. Combined treatment with cisplatin and trichostatin A or vorinostat had a synergistic effect on cancer-cell death. Conclusions: This study revealed that DNA methylation maintains CLDN1 expression and then represses lung cancer progression via the CLDN1-EPHB6-ERK1/2-SLUG axis. Because CLDN1 enhances the efficacy of chemotherapy, CLDN1 is not only a prognostic marker but a predictive marker for lung adenocarcinoma patients who are good candidates for chemotherapy. Forced CLDN1 expression in low CLDN1-expressing lung adenocarcinoma will increase the chemotherapy response, providing a novel therapeutic strategy.
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PMID:DNA methylation maintains the CLDN1-EPHB6-SLUG axis to enhance chemotherapeutic efficacy and inhibit lung cancer progression. 3275 86

Triple-negative breast cancers (TNBCs) lack ER, PR and her2 receptors that are targets of common breast cancer therapies with poor prognosis due to their high rates of metastasis and chemoresistance. Based on our previous studies that epigenetic silencing of a potential metastasis suppressor, arrestin domain-containing 3 (ARRDC3), is linked to the aggressive nature of TNBCs, we identified a sub-group of tumor suppressing miRNAs whose expressions were significantly up-regulated by ARRDC3 over-expression in TNBC cells. Among these tumor suppressing miRs, we found that miR-489 is most anti-proliferative in TNBC cells. miR-489 also blocked DNA damaging responses (DDRs) in TNBC cells. To define the mechanism by which miR-489 inhibits TNBC cell functions, we screened the potential target genes of miR-489 and identified MDC-1 and SUZ-12 as novel target genes of miR-489 in TNBC cells. To further exploit the therapeutic potentials of miR-489 in TNBC models, we chemically modified the guide strand of miR-489 (CMM489) by replacing Uracil with 5-fluorouracil (5-FU) so that tumor suppressor (miR-489) and DNA damaging (5-FU) components are combined into a single agent as a novel drug candidate for TNBCs. Our studies demonstrated that CMM489 shows superior effects over miR-489 or 5-FU in inhibition of TNBC cell proliferation and tumor progression, suggesting its therapeutic efficacy in TNBC models.
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PMID:Therapeutic Potential of Chemically Modified miR-489 in Triple-Negative Breast Cancers. 3278

The most frequent genetic alterations across multiple human cancers are mutations in TP53 and the activation of the PI3K/AKT pathway, two events crucial for cancer progression. Mutations in TP53 lead to the inhibition of the tumour and metastasis suppressor TAp63, a p53 family member. By performing a mouse-human cross species analysis between the TAp63 metastatic mammary adenocarcinoma mouse model and models of human breast cancer progression, we identified two TAp63-regulated oncogenic lncRNAs, TROLL-2 and TROLL-3. Further, using a pan-cancer analysis of human cancers and multiple mouse models of tumour progression, we revealed that these two lncRNAs induce the activation of AKT to promote cancer progression by regulating the nuclear to cytoplasmic translocation of their effector, WDR26, via the shuttling protein NOLC1. Our data provide preclinical rationale for the implementation of these lncRNAs and WDR26 as therapeutic targets for the treatment of human tumours dependent upon mutant TP53 and/or the PI3K/AKT pathway.
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PMID:Pan-cancer analysis reveals TAp63-regulated oncogenic lncRNAs that promote cancer progression through AKT activation. 3305 90

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