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Oncogenic retinoic acid receptor ? knockdown reverses multi-drug resistance of human colorectal cancer via Wnt/?-catenin pathway.

ABSTRACT: Retinoic acid receptor ? (RAR?), a unique member of the nuclear receptor superfamily, plays an important role in the progression of several cancers such as hepatocellular carcinoma, esophageal cancer, and cholangiocarcinoma. However, little is known about the regulatory mechanism of the RAR? expression in colorectal cancer (CRC) progression. In the present study, we found that RAR? was frequently overexpressed in human CRC specimens and CRC cell lines, and it mainly resided in the cytoplasm in CRC specimens. Tissue microarrays showed that RAR? indicated vital clinical significance in CRC. RAR? knockdown neither affected CRC cell proliferation nor blocked the cell cycle of CRC cells. However, RAR? knockdown increased the sensitivity of CRC cells to chemotherapeutics through downregulation of multi-drug resistance 1(MDR1). Further studies suggested that RAR? knockdown resulted in downregulation of MDR1, in parallel with suppression of the Wnt/?-catenin pathway. Moreover, a significantly positive association between RAR? and MDR1 was demonstrated in CRC tissue microarrays. Collectively, these results suggested that overexpression of RAR? contributed to the multidrug chemoresistance of CRC cells, at least in part due to upregulation of MDR1 via activation of the Wnt/?-catenin pathway, indicating that RAR? might serve as a potential therapeutic target for chemoresistant CRC patients.

SUBMITTER: Huang GL

PROVIDER: S-EPMC5397258 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Oncogenic retinoic acid receptor γ knockdown reverses multi-drug resistance of human colorectal cancer via Wnt/β-catenin pathway.

Huang Gui-Li GL Song Wei W Zhou Pan P Fu Qi-Rui QR Lin Chen-Lu CL Chen Qing-Xi QX Shen Dong-Yan DY

Cell cycle (Georgetown, Tex.) 20170308 7

Retinoic acid receptor γ (RARγ), a unique member of the nuclear receptor superfamily, plays an important role in the progression of several cancers such as hepatocellular carcinoma, esophageal cancer, and cholangiocarcinoma. However, little is known about the regulatory mechanism of the RARγ expression in colorectal cancer (CRC) progression. In the present study, we found that RARγ was frequently overexpressed in human CRC specimens and CRC cell lines, and it mainly resided in the cytoplasm in C ...[more]

PMID: 28272990

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Project description:Aberrant regulation of the Wnt/?-catenin signaling pathway is one of the major causes of colorectal cancer (CRC). Loss-of-function mutations in APC are commonly found in CRC, leading to inappropriate activation of canonical Wnt signaling. Conversely, gain-of-function mutations in KRAS and BRAF genes are detected in up to 60% of CRCs. Whereas KRAS/mitogen-activated protein kinase (MAPK) and canonical Wnt/?-catenin pathways are critical for intestinal tumorigenesis, mechanisms integrating these two important signaling pathways during CRC development are unknown. Results herein demonstrate that transformation of normal intestinal epithelial cells (IECs) by oncogenic forms of KRAS, BRAF or MEK1 was associated with a marked increase in ?-catenin/TCF4 and c-MYC promoter transcriptional activities and mRNA levels of c-Myc, Axin2 and Lef1. Notably, expression of a dominant-negative mutant of T-Cell Factor 4 (?NTCF4) severely attenuated IEC transformation induced by oncogenic MEK1 and markedly reduced their tumorigenic and metastatic potential in immunocompromised mice. Interestingly, the Frizzled co-receptor LRP6 was phosphorylated in a MEK-dependent manner in transformed IECs and in human CRC cell lines. Expression of LRP6 mutant in which serine/threonine residues in each particular ProlineProlineProlineSerine/ThreonineProline motif were mutated to alanines (LRP6-5A) significantly reduced ?-catenin/TCF4 transcriptional activity. Accordingly, MEK inhibition in human CRC cells significantly diminished ?-catenin/TCF4 transcriptional activity and c-MYC mRNA and protein levels without affecting ?-catenin expression or stability. Lastly, LRP6 phosphorylation was also increased in human colorectal tumors, including adenomas, in comparison with healthy adjacent normal tissues. Our data indicate that oncogenic activation of KRAS/BRAF/MEK signaling stimulates the canonical Wnt/?-catenin pathway, which in turn promotes intestinal tumor growth and invasion. Moreover, LRP6 phosphorylation by ERK1/2 may provide a unique point of convergence between KRAS/MAPK and Wnt/?-catenin signalings during oncogenesis.

Project description:Background:Mishandling of intracellular chloride (Cl-) concentration ([Cl-]i) in cerebrovascular smooth muscle cells is implicated in several pathological processes, including hyperplasia and remodeling. We investigated the effects of ClC-2-mediated Cl- efflux on the proliferation of human brain vascular smooth muscle cells (HBVSMCs) induced by angiotensin II (AngII). Methods:Cell proliferation and motility were determined using the CCK-8, bromodeoxyuridine staining, wound healing and invasion assays. ClC-2, PCNA, Ki67, survivin and cyclin D1 expression, and ?-catenin and GSK-3? phosphorylation were examined using western blotting. Histological analyses were performed using hematoxylin and eosin staining and ?-SMA staining. Results:Our results showed that AngII-induced HBVSMC proliferation was accompanied by a decrease in [Cl-]i and an increase in ClC-2 expression. Inhibition of ClC-2 by siRNA prevented AngII from inducing the efflux of Cl-. AngII-induced HBVSMC proliferation, migration and invasion were significantly attenuated by ClC-2 downregulation. The inhibitory effects of ClC-2 knockout on HBVSMC proliferation and motility were associated with inactivation of the Wnt/?-catenin signaling pathway, as evidenced by inhibition of ?-catenin phosphorylation and nuclear translocation, and decrease of GSK-3? phosphorylation and survivin and cyclin D1 expression. Recombinant Wnt3a treatment markedly reversed the effect of ClC-2 knockdown on HBVSMC viability. An in vivo study revealed that knockdown of ClC-2 with shRNA adenovirus ameliorated basilar artery remodeling by inhibiting Wnt/?-catenin signaling in AngII-treated mice. Conclusion:This study demonstrates that blocking ClC-2-mediated Cl- efflux inhibits AngII-induced cerebrovascular smooth muscle cell proliferation and migration by inhibiting the Wnt/?-catenin pathway. Our data indicate that downregulation of ClC-2 may be a viable strategy in the prevention of hyperplasia and remodeling of cerebrovascular smooth muscle cells.

Dataset Information

Oncogenic retinoic acid receptor ? knockdown reverses multi-drug resistance of human colorectal cancer via Wnt/?-catenin pathway.

Publications

Oncogenic retinoic acid receptor γ knockdown reverses multi-drug resistance of human colorectal cancer via Wnt/β-catenin pathway.

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