ABSTRACT
Obesity increases the incidence, progression and mortality of breast cancer among postmenopausal females. This is partly due to excessive estrogen production in the adipose tissue of obese females. Aromatase is a key enzyme in estrogen biosynthesis. In the current study, the tensional forcetriggered inducibility of aromatase expression was observed to vary in ASCs isolated from different diseasefree individuals. In addition, this phenomenon was associated with the activation of the aromatase PII promoter and its DNA methylation load. These findings highlight the impact of tensional forces on estrogen biosynthesis in obese females.
Subject(s)
Adipose Tissue/enzymology , Aromatase/metabolism , DNA Methylation , Adipose Tissue/cytology , Aromatase/genetics , Azacitidine/analogs & derivatives , Azacitidine/pharmacology , Cell Culture Techniques , Cells, Cultured , CpG Islands , Decitabine , Enzyme Activation/drug effects , Female , Humans , Obesity/metabolism , Obesity/pathology , Promoter Regions, Genetic , RNA, Messenger/metabolismABSTRACT
Metastasis is the leading cause of cancer-related death in almost all types of cancers, including colorectal cancer (CRC). Metastasis is a complex, multistep, dynamic biological event, and epithelial-mesenchymal transition (EMT) is a critical process during the cascade. Ajuba family proteins are LIM domain-containing proteins and are reported to be transcription repressors regulating different kinds of physiological processes. However, the expression and pathological roles of Ajuba family proteins in tumors, especial in tumor metastasis, remain poorly studied. Here, we found that JUB, but not the other Ajuba family proteins, was highly upregulated in clinical specimens and CRC cell lines. Ectopic expression of JUB induced EMT and enhanced motility and invasiveness in CRC, and vice versa. Mechanistic study revealed that JUB induces EMT via Snail and JUB is also required for Snail-induced EMT. The expression of JUB shows an inverse correlation with E-cadherin expression in clinical specimens. Taken together, these findings revealed that the LIM protein JUB serves as a tumor-promoting gene in CRC by promoting EMT, a critical process of metastasis. Thus, the LIM protein JUB may provide a novel target for therapy of metastatic CRC.
Subject(s)
Colorectal Neoplasms/pathology , Epithelial-Mesenchymal Transition , LIM Domain Proteins/metabolism , Caco-2 Cells , Cadherins/biosynthesis , Cell Movement , Colorectal Neoplasms/genetics , HCT116 Cells , Humans , LIM Domain Proteins/genetics , Neoplasm Invasiveness , Neoplasm Metastasis , RNA Interference , RNA, Small Interfering , Signal Transduction , Snail Family Transcription Factors , Spheroids, Cellular/pathology , Transcription Factors/metabolism , Tumor Cells, Cultured , Up-RegulationABSTRACT
Hepatocellular carcinoma (HCC) is one of the most common human malignancies and the third leading cause of cancer mortality worldwide. The development and progression of HCC is a complicated process, involving the deregulation of multiple genes that are essential to cell biological processes. Recently, microRNAs (miRNAs) have been suggested to be closely associated with tumorigenesis. Our study showed that miR-184 is upregulated in HCC cell lines and tissues. Overexpression of miR-184 in HCC cells increased cell proliferation, tumorigenicity, and cell cycle progression, whereas inhibition of miR-184 reduced cell proliferation, tumorigenicity, and cell cycle progression. Additionally, we identified SOX7 as a direct target of miR-184. Ectopic expression of miR-184 led to downregulation of the SOX7 protein, resulting in upregulation of c-Myc, Cyclin D1, and phosphorylation of Rb. Our findings suggested that miR-184 represents a potential onco-miR and plays an important role in HCC progression by suppressing SOX7 expression.
Subject(s)
Carcinoma, Hepatocellular/pathology , Gene Expression Regulation, Neoplastic/genetics , Liver Neoplasms/pathology , MicroRNAs/genetics , SOXF Transcription Factors/genetics , Base Sequence , Carcinogenesis/genetics , Cell Cycle/genetics , Cell Line, Tumor , Cell Proliferation , Humans , RNA, Messenger/genetics , RNA, Messenger/metabolismABSTRACT
BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers worldwide and a leading cause of cancer related death. Although the mortality rate of CRC is decreasing, finding novel targets for its therapy remains urgent. Carboxypeptidase E (CPE), a member of the pro-protein convertases, which are involved in the maturation of protein precursors, has recently been reported as elevated in many types of cancer. However, its role and mechanisms in tumor progression are poorly understood. METHODS: In the present study, we investigated expression of CPE in CRC cell lines and tumor tissues using Western blot and real-time qRT-PCR. Plasmids for overexpression and depletion of CPE were constructed and analyzed by Western blot, MTT and colony formation assays and bromodeoxyuridine incorporation assays. The relative expression of p21, p27, and cyclin D1 were analyzed by Real-time qRT-PCR in the indicated cells. RESULTS: Our study showed that CPE was significantly upregulated in CRC cell lines and tumor tissues. MTT and colony formation assays indicated that overexpression of CPE enhanced cell growth rates. BrdU incorporation and flow-cytometry assays showed that ectopic expression of CPE increased the S-phase fraction cells. Soft agar assay proved enhanced tumorigenicity activity in CPE over-expressing CRC cells. Further studies of the molecular mechanisms of CPE indicated that is promoted cell proliferation and tumorigenicity through downregulation of p21 and p27, and upregulation of cyclin D1. CONCLUSIONS: Taken together, these data suggest that CPE plays an important role in cell cycle regulation and tumorigenicity, and may serve as a potential target for CRC therapeutics.
