Molecular basis for the involvement of thymidine phosphorylase in cancer invasion
Takenari GotandaMisako HaraguchiTokushi TachiwadaReiko ShinkuraChihaya KoriyamaSuminori AkibaMotoshi KawaharaKenryu NishiyamaTomoyuki SumizawaTatsuhiko FurukawaHiromitsu MimataYoshio NomuraShin‐ichi AkiyamaMasayuki Nakagawa
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Thymidine phosphorylase (TP), also known as platelet-derived endothelial cell growth factor (PD-ECGF), has been implicated in bladder cancer angiogenesis and invasion. However, the molecular basis of its role in invasion remains unclear. We investigated the expression of TP and 10 invasion-related genes in bladder cancers from 72 randomly selected patients by real-time two-step RT-PCR assay. We found that the expression levels of TP, MMP-9, uPA, and MMP-2 were significantly higher in invasive tumors than those in superficial tumors. Also, the expression level of TP significantly correlated with that of uPA, MMP-1, MMP-9, PAI-1 and VEGF. KK47/TP cells, bladder cancer cells that overexpress TP, had a higher expression of MMP-7 and MMP-9 than KK/CV cells that express lower level of TP in hypoxic condition. PC/TP cells, prostate cancer cells that overexpress TP, also had a higher expression of MMP-1 and MMP-7 than PC/CV cells that express no detectable TP. Taken together these data indicate that TP enhances the invasion of tumor cells through the induction of invasion-related genes.Keywords:
Thymidine phosphorylase
Renal cell carcinoma (RCC) is one of the most common urinary tumors. Previous studies have demonstrated that microRNA (miR)‑181a‑5p has an important role in numerous types of cancer. However, the function of miR‑181a‑5p in RCC remains unknown. In the present study, the expression levels of miR‑181a‑5p in RCC tissues and cell lines were investigated using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) analysis. The results of the RT‑qPCR analyses suggested that the expression of miR‑181a‑5p was upregulated in RCC tissues and cells lines compared with adjacent normal renal tissues and normal renal cell lines. Furthermore, the effect of miR‑181a‑5p on cell proliferation, migration, invasion and apoptosis was investigated in the present study. Overexpression of miR‑181a‑5p was revealed to suppress the apoptosis of 786‑O and ACHN cells, in addition to enhancing the proliferation, migration and invasion abilities of 786‑O and ACHN cells in vitro, thus suggesting that miR‑181a‑5p may function as an oncogene in RCC. However, further studies are required to investigate the underlying mechanism of miR‑181a‑5p and its potential role as a biomarker for early detection and prognosis, in addition to as a therapeutic target in RCC.
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Aminoacylase 1 (ACY1) is important for regulating the proliferation of numerous types of cancer. However, the expression and mechanisms underlying the function of ACY1 in colorectal cancer remain unclear. In order to investigate the expression and function of ACY1 in colorectal cancer, tumor tissue and blood samples were collected for analysis from 132 patients diagnosed with colorectal cancer. Reverse transcription-quantitative polymerase chain reaction analysis and western blotting identified significantly increased expression of ACY1 mRNA in colorectal tumor tissue (P<0.05 vs. adjacent normal tissue) and notably increased ACY1 protein levels. This ACY1 mRNA expression was found to be positively correlated with tumor stage. In addition, plasma ACY1 concentration was increased in patients with colorectal cancer compared with healthy controls. Furthermore, in vitro knockdown of ACY1 in human colorectal cancer HT-29 cells was shown to inhibit proliferation and increase apoptosis. This effect was found to be associated with the activation of ERK1 and TGF-β1 signaling. In conclusion, the results of the present study suggest that ACY1 promotes tumor progression, and thus may be a potential target for the diagnosis and treatment of colorectal cancer.
Expression (computer science)
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Previous studies have demonstrated that microRNA (miR)-23a-3p plays a role as an oncogene that is involved in several different types of carcinoma. However, few studies investigated the association between miR-23a-3p and pancreatic cancer (PC). The aim of the present study was to elucidate the biological functions of miR-23a-3p in PC and to investigate its underlying molecular mechanisms. The expression of miR-23a-3p in PC and adjacent normal tissues was investigated using microarrays. In order to validate the outcomes of the microarray results, reverse transcription-quantitative (RT-q)PCR was used to determine the expression levels of miR-23a-3p in PC tissues and cell lines. Furthermore, functional analyses were conducted following miR-23a-3p inhibition and overexpression, in order to assess the proliferation, invasion and migration of PC cells. Bioinformatics analysis indicated transforming growth factor-β receptor type II (TGFBR2) as a potential direct target of miR-23a-3p. Western blotting was performed in order to determine the protein expression of TGFBR2 in PC cell lines. The findings from the microarray demonstrated upregulation of miR-23a-3p in PC compared with normal tissues. RT-qPCR revealed significantly higher levels of miR-23a-3p expression in PC compared with normal control tissues or cells. Furthermore, miR-23a-3p was demonstrated to promote the proliferation, invasion and migration of PC cells, which was suppressed by the inhibition of miR-23a-3p. In addition, the miR-23a-3p expression level was negatively associated with TGFBR2 expression. Overall, the present study demonstrated the tumor-promoting effects of miR-23a-3p in PC cells. Furthermore, miR-23a-3p is a potential oncogenic regulator of PC, by targeting TGFBR2, and a biomarker or target for molecular therapy.
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The expression of microRNA-203 (miR-203) in esophageal squamous cell carcinoma (ESCC) tissues is remarkably lower than that in non‑ESCC tissues. We investigated how miR-203 could influence the development of ESCC cells. Our analyses revealed that miR-203 inhibited the migration and invasion of ESCC cells. Genome-wide gene expression data and target site inhibition assays showed that miR-203 appears to directly regulate LIM and SH3 protein 1 (LASP1). The knockdown of LASP1 resulted in inhibition of the migration and invasion of ESCC cells. Our results suggest that miR-203 and its target LASP1, may be associated with the progression of ESCC. In clinical ESCC specimens, the expression levels of miR-203, which were lower compared to those in normal tissues, were inversely correlated with the mRNA expression levels of LASP1. Moreover, we found that there was a significant correlation between the expression levels of miR-203 and the relapse‑free survival. The identification of a cancer network regulated by miR-203 could provide new insights into the potential mechanisms of the progression of ESCC.
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原発性肺癌手術症例242例を対象とし, マトリックスメタロプロテイナーゼ (MMP), メタロプロテイナーゼインヒビター (TIMP), およびthymidine phosphorylase (TP) の発現を免疫組織化学的に検出し, 特に予後との関連について検討した.全症例におけるMMP-2・9, TIMP-2, TPでは陰性群が陽性群に対して有意に高い無再発生存率を示した. I期症例144例での検討ではMMP-2・9, TPにおいて陰性群が陽性群に対して有意に高い無再発生存率を示した. I期症例のうち, 腺癌ではMMP-2・9陰性群が陽性群に対して有意に高い無再発生存率を示したが, 扁平上皮癌では差はみられなかった.多変量解析の結果, MMP-9, N因子, T因子が有意に独立した予後因子と判断された. これら各因子の検索は, 今後臨床において, より的確な予後の想定, 補助療法等の治療方針の決定に有用であると考えられた.
Thymidine phosphorylase
Thymidine
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Esophageal squamous cell carcinoma (ESCC) is a common malignancy and one of the more difficult diseases to diagnose in Japan due to its poor prognosis. MicroRNAs are small non-coding RNAs of 21-23 nucleotides that regulate gene expression. MicroRNA-34b (miR-34b) has been reported to be overexpressed in various types of cancer. However, its role in ESCC has yet to be extensively studied. The present study investigated the expression of miR-34b in 88 ESCC patients. The miR-34b expression in ESCC was significantly higher than that in the corresponding normal esophageal mucosa. It was more highly expressed in tumors with more advanced stages. However, its expression did not correlate with the p53 status. Transfection of anti-miR-34b to the ESCC cells suppressed cell growth in vitro. These results suggest an oncogenic role of miR in ESCC.
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