Dysregulated protease activated receptor 1 (PAR1) promotes metastatic phenotype in breast cancer through HMGA2
Eric YangJarosław CisowskiNga NguyenKatie O’CallaghanJian XuAnika AgarwalAthan KuliopulosLidija Covic
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HMGA2
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Long non‑coding RNAs (lncRNAs) and microRNAs (miRs) have been reported to regulate disease progression in numerous types of disease, including retinoblastoma (Rb). Therefore, the present study aimed to investigate the effects of the lncRNA FEZ family zinc finger 1 antisense RNA 1 (FEZF1‑AS1) on Rb and to determine its possible mechanism of action. Reverse transcription‑quantitative PCR and western blot analysis were conducted to detect the gene or protein expression. Cell Counting Kit‑8, wound healing and transwell invasion assays were performed to estimate the capabilities of cell viability, invasion and migration. The potential association between FEZF1‑AS1 and miR‑1236‑3p in Y79 cells was measured via dual‑luciferase reporter assay. The results of the present study revealed that the levels of FEZF1‑AS1 were significantly upregulated in different Rb cell lines, with the most prominent upregulation observed in Y79 cells. In addition, the cell viability, invasive and migratory abilities, and the ability to undergo epithelial‑mesenchymal transition (EMT), were significantly inhibited following the transfection of short hairpin RNA (shRNA)‑FEZF1‑AS1 into Y79 cells. Further experimental validation confirmed that miR‑1236‑3p may be a direct target of FEZF1‑AS1. Notably, the miR‑1236‑3p inhibitor was discovered to reverse the inhibitory effects of shRNA‑FEZF1‑AS1 on cell viability, invasion, migration and EMT. In conclusion, the findings of the present study suggested that lncRNA‑FEZF1‑AS1 may promote the viability, migration, invasion and EMT of Rb cells by modulating miR‑1236‑3p.
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Tumor metastases are the ultimate target in cancer therapy. In epithelial malignancies, the expression of high-mobility-group A2 (HMGA2) is associated with disease progression and the epithelial-mesenchymal transition (EMT), which is involved in the metastatic process. The present study assessed the clinical and molecular effects of HMGA2 with the malignant tissues of 170 patients with gastric cancer and gastric cancer cells expressing HMGA2. HMGA2 expression was determined using immunohistochemistry and analyzed with respect to the clinicopathological data of patients with this tumor. In the gastric cancer cell line MKN28, in which HMGA2 was knocked down by two different short-hairpin RNAs, Transwell migration and invasion assays were conducted and western blotting was used to detect the altered expression of EMT markers. In patients with gastric cancer, HMGA2 overexpression correlated with tumor progression and was indicative of a significantly worse overall survival. Migration and invasion assays using HMGA2-knocked down MKN28 cells showed a reduction in cell migration and invasion. The upregulation of E-cadherin, an epithelial marker, and the downregulation of N-cadherin, a mesenchymal marker were observed in HMGA2-knocked down cells. In addition, expression of the transcriptional factors Snail and Zeb1 and of the EMT-pathway molecule β-catenin were decreased. HMGA2 overexpression, through its relationship to EMT, thus seems to aggravate invasion and metastasis in gastric cancer. It may therefore serve as a predictive marker in determining the clinical outcome of patients with gastric cancer and offer a promising therapeutic target.
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Abstract The aim of our study was first to assess the role of HMGA2 expression in the pathogenesis of adipocytic tumors (AT) and, second, to seek a potential correlation between overexpression of HMGA2 and let‐7 expression inhibition by analyzing a series of 56 benign and malignant AT with molecular cytogenetic data. We measured the levels of expression of HMGA2 mRNA and of eight members of the let‐7 microRNA family using quantitative RT‐PCR and expression of HMGA2 protein using immunohistochemistry. HMGA2 was highly overexpressed in 100% of well‐differentiated/dedifferentiated liposarcomas (WDLPS/DDLPS), all with HMGA2 amplification, and 100% of lipomas with HMGA2 rearrangement. Overexpression of HMGA2 mRNA was detected in 76% of lipomas without HMGA2 rearrangement. HMGA2 protein expression was detected in 100% of lipomas with HMGA2 rearrangement and 48% of lipomas without HMGA2 rearrangement. We detected decreased expression levels of some let‐7 members in a significant proportion of AT. Notably, let‐7b and let‐7g were inhibited in 61% of WDLPS/DDLPS. In lipomas, each type of let‐7 was inhibited in approximately one‐third of the cases. Although overexpression of both HMGA2 mRNA and protein in a majority of ordinary lipomas without HMGA2 structural rearrangement may have suggested a potential role for let‐7 microRNAs, we did not observe a significant link with let‐7 inhibition in such cases. Our results indicate that inhibition of let‐7 microRNA expression may participate in the deregulation of HMGA2 in AT but that this inhibition is neither a prominent stimulator for HMGA2 overexpression nor a surrogate to genomic HMGA2 rearrangements. © 2011 Wiley‐Liss, Inc.
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Estrogen is proven to promote the malignant behaviors of many cancers via its receptors. Estrogen receptor alfa 36 (ER-α36) is a newly identified isoform of estrogen receptor alfa (ER-α), the role of ER-α36 in regulating the effects of estrogen and its potential impact on human cervical cancer is poorly understood.Immunohistochemistry staining was used to evaluate the expression of ER-α36, estrogen receptor alfa 66 (ER-α66) and their prognostic values in cervical cancer. The effects of ER-α36 and ER-α66 on the proliferation and metastasis of cervical cancer were measured in vitro. A xenograft tumor assay was used to study the tumorigenesis role of ER-α36 in vivo. Furthermore, the functional gene at the downstream of ER-α36 was obtained via next-generation sequencing, and the biological functions of high mobility group A2 (HMGA2) in cervical cancer cells were investigated in vitro.ER-α36 was over-expressed in cervical cancer tissues and elevated ER-α36 expression was associated with poor prognosis in cervical cancer patients. High expression of ER-α36 promoted the proliferation, invasion and metastasis of cervical cancer cells mediated by estrogen, while silencing ER-α36 had the opposite effects. Further research showed that HMGA2 was a downstream target of ER-α36 in cervical cancer cells. The oncogenic effect of ER-α36 was attenuated after HMGA2 knockdown.High expression of ER-α36 was correlated with a poor prognosis in cervical cancer by regulating HMGA2. ER-α36 could be a prognostic biomarker and a target for cervical cancer treatment.
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Estrogen receptor alpha
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Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the data shown for the Transwell cell migration and invasion assays in Figs. 2C and 4C were strikingly similar to data appearing in different form in another article by different authors at a different research institution. Owing to the fact that the contentious data in the above article were under consideration for publication elsewhere at a similar time to when it was submitted to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive any reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 17: 2712‑2718, 2018; DOI: 10.3892/mmr.2017.8131].
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Zinc finger protein 24 (ZNF24) has been demonstrated to regulate proliferation, differentiation and migration as well as invasion in several types of cells. However, the molecular role and clinical effects of ZNF24 in prostate cancer (PCa) remain unclear. The present study revealed that ZNF24 expression is upregulated in PCa, and associated with tumor volume, Gleason score, pathological grade and metastasis. Wound healing and Transwell invasion assays revealed that ectopic ZNF24 expression facilitated cell migration and invasion through the Twist1-induced epithelial-to-mesenchymal transition (EMT) process. In addition, colony formation and Cell Counting Kit-8 assays were used to determine the regulatory effects of ZNF24 on proliferation. The results suggested that ZNF24 also promoted cell proliferation in PCa. ZNF24 acted as an oncogene and promoted migration, invasion and EMT of PCa cells via the regulation of Twist1.
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MicroRNAs (miRNAs) are a class of small, single-stranded, non-coding RNA molecules which can act as oncogenes or tumor suppressor genes in human cancer. However, the possible functions and mechanisms of miRNA action in gallbladder cancer (GBC) have not been elucidated. In the present study, it was found that miR-26a was often downregulated in GBC and the expression of miR-26a was associated with neoplasm histological grade. miR-26a significantly inhibited the proliferation of GBC cells based on the gain-of-function assays. Furthermore, we demonstrated that high mobility group AT-hook 2 (HMGA2) was a direct target of miR-26a. The results showed that HMGA2 mRNA levels and miR-26a levels were negatively correlated. In addition, we confirmed that reintroduction of HMGA2 antagonized the inhibition of miR-26a to GBC cell proliferation and all these effects were achieved through the cell cycle. Together, all these results suggest that miR-26a expression contributes to GBC proliferation by targeting HMGA2. miR-26a shows promise as a prognosis factor and therapeutic target of GBC patients.
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High-mobility group AT-hook 2 (HMGA2), a member of the high mobility group family, has been reported to correlate with cancer progression. However, there is no report concerning the correlation between HMGA2 and metastasis in renal cell carcinoma. In the present study, we found that HMGA2 was highly expressed in five renal cell carcinoma cell lines compared with that in the normal renal tubular epithelial HK2 cell line. Additionally, HMGA2 facilitated cell migration and invasion of renal cell carcinoma cells, as evidenced by wound healing and Transwell assays. Subsequently, our results revealed that the E‑cadherin level was upregulated, while N‑cadherin, Twist1 and Twist2 expression were downregulated in HMGA2-depleted ACHN cells. In contrast, overexpression of HMGA2 in 786‑O cells enhanced epithelial-mesenchymal transition (EMT). In addition, analysis of the database Cancer Browser further validated the positive correlation between HGMA2 and Twist1 or Twist2 in renal cell carcinoma. Meanwhile, Kaplan-Meier analysis indicated that low HMGA2 expression was closely associated with an increased overall survival in renal cell carcinoma patients. To confirm the underlying mechanism of HMGA2-regulated EMT, our results revealed that silencing of HMGA2 downregulated the mRNA and protein levels of TGF-β and Smad2, while HMGA2 overexpression had the opposite effect. Furthermore, TGF-β overexpression could partially reverse the anti-metastatic effect and mesenchymal-epithelial transition (MET) by HMGA2 loss, while TGF-β deficiency impeded the pro‑metastatic phenotype and high expression of EMT markers induced by HMGA2 overexpression. In summary, our results demonstrated that HMGA2 facilitated a metastatic phenotype and the EMT process in renal cell carcinoma cells in vitro through a TGF-β-dependent pathway. In addition, these data strongly suggest that HGMA2 may serve as a potential therapeutic target and prognostic biomarker against renal cell carcinoma in the future.
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