PAR2 Inhibition Enhanced the Sensitivity of Colorectal Cancer Cells to 5-FU and Reduced EMT Signaling

Quan, Qiuying; Zhong, Fengyun; Wang, Xinwei; Chen, Kai; Guo, Linxin

doi:10.3727/096504018x15442985680348

Cited by 19 publications

(15 citation statements)

References 29 publications

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“…Romano et al found that 5-FU activated TGF-β pathway and the transcription of ACVRL1, FN1 and TGFB1 in drug resistant colorectal carcinoma cells [11]. In line with our results, a recent publication showed that PAI-1 expression was elevated in CRC tissue biopsies after 5-FU chemotherapy administration [40]. Also, Robinson et al showed increased expression of PAI-1 in the liver of tumor-bearing FOLFOX-treated mice in comparison to vehicle treated control mice [41].…”

Section: Discussionsupporting

confidence: 92%

Effects of Chemotherapy for Metastatic Colorectal Cancer on the TGF-β Signaling and Related miRNAs hsa-miR-17-5p, hsa-miR-21-5p and hsa-miR-93-5p

Despotović

Dragičević

Nikolić

2021

Cell Biochem Biophys

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Metastatic colorectal cancer (mCRC) patients are treated with standard chemotherapeutic drugs in the form of FOLFOX and FOLFIRI regimens. There are no reliable markers that could predict response to chemotherapy for mCRC. TGF-β signaling which interacts with microRNA (miRNA) network has important roles in tumor progression and chemotherapy resistance, thus the interplay between TGF-β signaling and miRNAs could be crucial for treatment response. The aim of this study was to analyze the effect of chemotherapy for mCRC on TGF-β signaling and related miRNAs. Hsa-miR-17-5p, hsa-miR-21-5p and hsa-miR-93-5p were selected out of 316 miRNAs with multiple targets within the TGF-β signaling by in silico analysis. SW620 cells were treated with chemotherapeutic drugs for mCRC for 1, 3 and 6 days and expression of selected miRNAs, PAI-1, CDH1 and VIM was measured. Expression of TGF-β signaling-related hsa-miR-17-5p, hsa-miR-21-5p and hsa-miR-93-5p was time-dependently altered in SW620 cells treated with chemotherapeutics for mCRC. The expression of hsa-miR-93-5p remained downregulated after 6 days under combined treatments FOX and FIRI as well as the hsa-miR-17-5p expression under FIRI. Chemotherapy regimens for mCRC increased expression of a major TGF-β signaling target gene PAI-1, independently of the selected miRNAs expression. These treatments also increased the expression of epithelialmesenchymal transition (EMT) markers CDH1 and VIM on day 3 resulting in decrease of mesenchymal-like characteristics. However, their expression returned close to basal level on day 6. In conclusion, after initial response to chemotherapeutic drugs SW620 cells start to return close to the basal mesenchymal state while the long-term downregulated expression pattern of hsa-miR-93-5p and hsa-miR-17-5p makes them candidates worth testing as biomarkers for monitoring combined chemotherapeutic treatments therapy response in mCRC patients.Keywords Metastatic colorectal cancer • Chemotherapy • microRNA • TGF-β signaling • Epithelial-mesenchymal transition * Jovana Despotovic

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Section: Discussionsupporting

confidence: 92%

Effects of Chemotherapy for Metastatic Colorectal Cancer on the TGF-β Signaling and Related miRNAs hsa-miR-17-5p, hsa-miR-21-5p and hsa-miR-93-5p

Despotović

Dragičević

Nikolić

2021

Cell Biochem Biophys

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“…44 Inhibition of PAR2 suppresses EMT and promotes the chemo-resistance of CRC to 5-FU. 45 Previous study showed that AQP5 silencing has an anti-cancer effect via regulating Wnt/β-catenin pathway and EMT progress, 46,47 which is consistent with our research. Additionally, AQP5 promotes hepatocellular carcinoma metastasis via modulating NF-κB-regulated EMT progress.…”

Section: Discussionsupporting

confidence: 91%

MiR-185-3p mimic promotes the chemosensitivity of CRC cells via AQP5

Zhou

Kong

et al. 2020

Cancer Biology & Therapy

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Background: Studies showed that microRNAs (miRNAs) are important regulators in drug resistance. The current study investigated the role of miR-185-3p and its predicted target gene AQP5 in 5-FU-insensitive colorectal cancer (CRC) cells. Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) and Spearman's correlation analysis were conducted to determine the correlation of expression levels of miR-185-3p and AQP5 from CRC tissues. HCT-116 and HCT-8 cells were treated by gradient concentration of 5-FU to construct 5-FU-resistant CRC model. The inhibition and viability of 5-FU-resistant cells were detected by MTT assay, and cell migration and invasion ability were determined by wound healing and transwell assay. The expressions of miR-185-3p and AQP5 were measured by qRT-PCR. StarBase and dual-luciferase reporter assay were used to predict and confirm the interaction between miR-185-3p and AQP5. Further experiments were performed to explore the function of miR-185-3p in 5-FU-resistant cells through regulating aquaporin-5 (AQP5). The levels of EMT-associated markers and AQP5 were determined by conducting Western Blot and qRT-PCR. Results: We found that 5-FU-resistant CRC cells showed a lower inhibition rate, and higher migration and invasion abilities. MiR-185-3p was low-expressed in CRC tissues and 5-FU-resistance cells, and it targeted and regulated the expression of AQP5, which was found up-regulated in CRC and 5-FU-resistance CRC cells (r = −0.29, P < .05). Furthermore, miR-185-3p mimic enhanced the chemo-sensitivity of 5-FU-resistant cells, while overexpressed AQP5 reversed such an effect produced by miR-185-3p mimic. Conclusion: MiR-185-3p mimic enhances the chemosensitivity of CRC cells via AQP5. Our research provides a potential therapeutic target for 5-FU-resistant CRC cells.

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“…31 Another study reported that PAR2 is involved in EMT via TGF-β signaling in colorectal cancer cells. 26 In this study, the PAR2 agonist tended to increase the expression of EMT markers, such as α-SMA and vimentin, but had no effect on TGFB expression, indicating that PAR2 may induce EMT independent of the TGF-β pathway in canine MC cells. However, this study did not examine the level of proteins associated with TGF-β activation, such as Smads.…”

Section: Discussionmentioning

confidence: 47%

Protease-Activated Receptor-2 Is Associated With Adverse Outcomes in Canine Mammary Carcinoma

Kaji

Hori

et al. 2020

Vet Pathol

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Protease-activated receptor-2 (PAR2) is a G protein–coupled receptor that is activated by serine proteases. In humans, PAR2 is highly expressed in various cancers, including breast cancer, and is associated with cancer progression and metastasis. However, the expression and roles of PAR2 in canine mammary carcinoma remain unclear. The purpose of this study was to examine the expression of PAR2 in canine mammary carcinoma, the association between PAR2 expression and clinical characteristics, and the role of PAR2 in the metastatic phenotypes of tumor cells. Mammary carcinoma from 31 dogs and 10 normal mammary glands were included in this study, and used for immunohistochemical analysis of PAR2 expression. Normal mammary glands did not express PAR2. In contrast, mammary carcinomas showed PAR2 immunoreactivity in the cytoplasm, and its expression level varied between specimens from negative to strongly positive. The overall survival of dogs with high PAR2 expression was shorter than that of dogs with low PAR2 expression. Moreover, PAR2 expression level was associated with the presence of lymph node involvement, advanced clinical stage, and high histopathological grade. In vitro analyses revealed that a PAR2 agonist accelerated cell migration and invasion in a canine mammary carcinoma cell line. In addition, the PAR2 agonist induced epithelial-mesenchymal transition and actin polymerization. These results suggest that PAR2 expression plays a role in tumor progression and clinical outcomes in canine mammary carcinoma.

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PAR2 Inhibition Enhanced the Sensitivity of Colorectal Cancer Cells to 5-FU and Reduced EMT Signaling

Cited by 19 publications

References 29 publications

Effects of Chemotherapy for Metastatic Colorectal Cancer on the TGF-β Signaling and Related miRNAs hsa-miR-17-5p, hsa-miR-21-5p and hsa-miR-93-5p

Effects of Chemotherapy for Metastatic Colorectal Cancer on the TGF-β Signaling and Related miRNAs hsa-miR-17-5p, hsa-miR-21-5p and hsa-miR-93-5p

MiR-185-3p mimic promotes the chemosensitivity of CRC cells via AQP5

Protease-Activated Receptor-2 Is Associated With Adverse Outcomes in Canine Mammary Carcinoma

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