Hsp27 Regulates Epithelial Mesenchymal Transition, Metastasis, and Circulating Tumor Cells in Prostate Cancer (original) (raw)
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JNCI J Natl Cancer Inst-2013-Evensen-jnci-djt224
Background Cell migration is a critical determinant of cancer metastasis, and a better understanding of the genes involved will lead to the identification of novel targets aimed at preventing cancer dissemination. KIAA1199 has been shown to be upregulated in human cancers, yet its role in cancer progression was hitherto unknown. Methods Clinical relevance was assessed by examining KIAA1199 expression in human cancer specimens. In vitro and in vivo studies were employed to determine the function of KIAA1199 in cancer progression. Cellular localization of KIAA1199 was microscopically determined. SNAP-tag pull-down assays were used to identify binding partner(s) of KIAA1199. Calcium levels were evaluated using spectrofluorometric and fluorescence resonance energy transfer analyses. Signaling pathways were dissected by Western blotting. Student t test was used to assess differences. All statistical tests were two-sided. Results KIAA1199 was upregulated in invasive breast cancer specimens and inversely associated with patient survival rate. Silencing of KIAA1199 in MDA-MB-435 cancer cells resulted in a mesenchymal-to-epithelial transition that reduced cell migratory ability in vitro (75% reduction; P < .001) and decreased metastasis in vivo (80% reduction; P < .001). Gain-of-function assays further demonstrated the role of KIAA1199 in cell migration. KIAA1199-enhanced cell migration required endoplasmic reticulum (ER) localization, where it forms a stable complex with the chaperone binding immunoglobulin protein (BiP). A novel ER-retention motif within KIAA1199 that is required for its ER localization, BiP interaction, and enhanced cell migration was identified. Mechanistically, KIAA1199 was found to mediate ER calcium leakage, and the resultant increase in cytosolic calcium ultimately led to protein kinase C alpha activation and cell migration. Conclusions KIAA1199 serves as a novel cell migration-promoting gene and plays a critical role in maintaining cancer mesenchymal status. J Natl Cancer Inst Cell migration is a complicated and incompletely understood process required for cancer invasion (1). Cell migration is often a consequence of epithelial-to-mesenchymal transition (EMT) of cancer cells, which leads to a more aggressive phenotype. Reversal of EMT (mesenchymal-to-epithelial-transition) results in decreased cell migration (2). Identification of specific genes involved in cancer cell migration is critically important in preventing cancer dissemination (3). To identify novel genes involved in cancer cell invasion, we used a polymerase chain reaction-based suppression subtractive hybridization method, which has been demonstrated to be effective in isolating, normalizing, and enriching differentially expressed genes >1000-fold in a single round of hybridization (4). Because concanavalin A enhances cell surface proteolytic activity and cell migratory ability (3,5), differential gene expression in concanavalin A-treated HT-1080 human fibrosarcoma cells was examined. This approach resulted in the identification of a marked upregulation of a previously obscure gene, KIAA1199, which is reported in the Human Unidentified Gene-Encoded Large Proteins database. The current literature and sequence homology provide few clues as to the function of KIAA1199. Based on a publication that describes genetic mutations of KIAA1199 in families with nonsyndromic hearing loss, this gene appears to be essential for auditory function (6), although the function was not investigated. Clinical relevance of KIAA1199 in cancers has been highlighted by reports of increased KIAA1199 mRNA expression in human gastric and colorectal cancers; an association was shown between KIAA1199 expression level and disease stage/5-year survival rates (7,8). However, the function of KIAA1199 in cancer remains unknown. In this study, we discovered that KIAA1199 is a novel endoplasmic reticulum (ER) resident protein that plays a critical role in
D'armiento et al Cancer Res 2007
The normal expression pattern of HMGA2, an architectural transcription factor, is primarily restricted to cells of the developing mesenchyme before their overt differentiation during organogenesis. A detailed in situ hybridization analysis showed that the undifferentiated mesoderm of the embryonic lung expressed Hmga2 but it was not expressed in the newborn or adult lung. Previously, HMGA2 was shown to be misexpressed in a number of benign, differentiated mesenchymal tumors including lipomas, uterine leiomyomas, and pulmonary chondroid hamartomas. Here, we show that HMGA2 is misexpressed in pulmonary lymphangiomyomatosis (LAM), a severe disorder of unknown etiology consisting of lymphatic smooth muscle cell proliferation that results in the obstruction of airways, lymphatics, and vessels. Immunohistochemistry was done with antibodies to HMGA2 and revealed expression in lung tissue samples obtained from 21 patients with LAM. In contrast, HMGA2 was not expressed in sections of normal adult lung or other proliferative interstitial lung diseases, indicating that the expression of HMGA2 in LAM represents aberrant gene activation and is not due solely to an increase in cellular proliferation. In vivo studies in transgenic mice show that misexpression of HMGA2 in smooth muscle cells resulted in increased proliferation of these cells in the lung surrounding the epithelial cells. Therefore, similar to the other mesenchymal neoplasms, HMGA2 misexpression in the smooth muscle cell leads to abnormal proliferation and LAM tumorigenesis. These results suggest that HMGA2 plays a central role in the pathogenesis of LAM and is a potential candidate as a therapeutic target. [Cancer Res 2007;67(5):1902-9] Requests for reprints: Jeanine D
Up-Regulation of TWIST in Prostate Cancer and Its Implication as a Therapeutic Target
2005
Androgen-independent metastatic prostate cancer is the main obstacle in the treatment of this cancer. Unlike a majority of solid cancers, prostate cancer usually shows poor response to chemotherapeutic drugs. In this study, we have shown a potential novel target, TWIST, a highly conserved bHLH transcription factor, in the treatment of prostate cancer. Using malignant and nonmalignant prostate tissues, we found that TWIST expression was highly expressed in the majority (90%) of prostate cancer tissues but only in a small percentage (6.7%) of benign prostate hyperplasia. In addition, the TWIST expression levels were positively correlated with Gleason grading and metastasis, indicating its role in the development and progression of prostate cancer. Furthermore, down-regulation of TWIST through small interfering RNA in androgen-independent prostate cancer cell lines, DU145 and PC3, resulted in increased sensitivity to the anticancer drug taxol-induced cell death which was associated with decreased Bcl/Bax ratio, leading to activation of the apoptosis pathway. More importantly, inactivation of TWIST suppressed migration and invasion abilities of androgen-independent prostate cancer cells, which was correlated with induction of E-cadherin expression as well as morphologic and molecular changes associated with mesenchymal to epithelial transition. These results were further confirmed on the androgen-dependent LNCaP cells ectopically expressing the TWIST protein. Our results have identified TWIST as a critical regulator of prostate cancer cell growth and suggest a potential therapeutic approach to inhibit the growth and metastasis of androgen-independent prostate cancer through inactivation of the TWIST gene. (Cancer Res 2005; 65(12): 5153-62)
Telerman Amson Nature Reviews Cancer 2009
| How cells become malignant has preoccupied scientists for over a century. However, the converse question is also valid: are tumour cells capable of reverting from their malignant state? Askanazy's studies in 1907 indicated that teratoma cells could differentiate into normal somatic tissues and current evidence indicates that some tumour cells have acquired the molecular circuitry that results in the negation of chromosomal instability, translocations, oncogene activation and loss of tumour suppressor genes. Studying these extremely rare events of tumour reversion and deciphering these pathways, which involve SIAH1, presenilin 1, TSAP6 and translationally controlled tumour protein (TCTP), could lead to new avenues in cancer treatment. PERSPECTIVES 206 | MARch 2009 | VOluMe 9 www.nature.com/reviews/cancer
…, 2008
Publication View. 55582701. BMC Cancer BioMed Central (2008). Laure Voisin,; Catherine Julien,; StÃĐphanie Duhamel,; Kailesh Gopalbhai,; Isabelle Claveau,; Marc K Saba-el-leil,; Ian GaÃŦl Rodrigue-gervais,; Louis Gaboury,; Daniel Lamarre,; Mark Basik,; Sylvain Meloche. ...
Sambi and Szewczuk Transl Cancer Res 2017;6(Suppl 1)S15-S17. doi 10.21037tcr.2017.01.05.pdf
The KRAS gene, also known as Kristen rat sarcoma viral oncogene homolog, is a member of the Ras family of cell proliferation regulators and plays an important role in cancer progression upon the mutation induced activation of this gene (1). A significant role that they play is in a cell proliferation signaling cascade that involves receptor to nucleus signal transduction and therefore the activation of this pathway is under tight control (1,2). In normal cells, the Ras proteins exist in two forms: the active form, when the protein is bound to GTP and the inactive form when they are bound to GDP (1). The action of this signaling cascade is under the control of an enzyme located on the Ras protein, a GTPase, which cleaves the GTP molecule from the Ras protein and effectively prevents signal transduction to the nucleus by transforming it into the inactive GDP-bound Ras and halts the growth signals (2). The ratio between the inactive and active forms of the Ras protein maintain cell growth and proliferation in normal cells.