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ADIPOQ

The epithelial-to-mesenchymal transition (EMT) is a highly conserved physiological program involved in development and tissue repair; however, its aberrant activation has been implicated in accelerating the progression of a variety of cancers. In breast cancer, the microRNAs (miRNAs) miR-221 and miR-222 (miR-221/222) are differentially expressed in the clinically more aggressive basal-like subtype compared to luminal subtype of breast cancer and upregulation of miR-221/222 induces the EMT by targeting the 3' untranslated region (3'UTR) of the GATA family transcriptional repressor TRPS1 (tricho-rhino-phalangeal syndrome type 1). The complete mechanism through which miR-221/222 promotes the EMT, however, is not fully understood. We identified adiponectin receptor 1 (ADIPOR1), a receptor for the adipocytokine adiponectin, as a direct target of miR-221/222. ADIPOR1 is expressed at higher levels in the luminal compared to the basal-like subtype of breast cancer cell lines, which can be reduced by miR-221/222 targeting of its 3'UTR. In addition, miR-221/222 were negatively correlated with ADIPOR1 expression across breast cancer cell lines and tumors. ADIPOR1 depletion by siRNA in MCF10A cells induced the EMT and increased cell invasion. Depletion of ADIPOR1 by siRNA induced activation of the canonical nuclear factor-kappaB (NF-kappaB) and subsequent phosphorylation of signal transducer and activator of transcription 3 (STAT3) in an interleukin 6 (IL6)-dependent manner. Finally, overexpression of ADIPOR1 in the basal-like cell line, MDA-MB-231, attenuated cell invasion and promoted the mesenchymal-to-epithelial transition (MET). We conclude that ADIPOR1 negatively regulates EMT in breast cancer and provides an additional node by which miR-221/222 induces the EMT. These results suggest that ADIPOR1 may play an important role in breast cancer progression and metastasis, and could potentially offer an alternative therapeutic strategy for basal-like breast cancer patients.

BACKGROUND: Recent evidence suggests a particular role for obesity in prostate cancer (PCa) progression. Adiponectin (ADN) is a hormone secreted by adipose tissue and has a variety of functions including the inhibition of PCa cell proliferation. Although serum ADN levels have been identified to be related with carcinogenesis in a tissue-specific context, the exact role of endogenous ADN in PCa cells remains largely unknown. METHODS: Two tissue microarrays were constructed and immunohistochemistry (IHC) was utilized to detect ADN's expression in a cohort of 96 Chinese PCa patients with radical prostatectomy as well as 15 cases with Benign Prostatic Hyperplasia (BPH). MTS and transwell assays were applied to validate the effects of ADN on proliferation and invasive capacity of PCa cells. Real-time PCR and Western blot were performed to evaluate the expression at transcript and protein levels. Epigenetic modifications of ADN's promoter after TGF-beta1 treatment in 22RV1 cells was monitored by chromatin immunoprecipitation (ChIP). Methylation-Specific PCR (MSP) was performed to determine the methylation status of ADN's promoter. RESULTS: IHC showed decreased levels of ADN in 1 of 15 (6.7%) BPH cases, 6 of 27 (22.2%) PCa cases with low Gleason score (<7), 18 of 26 (69.2%) cases with Gleason score 7, but 32 of 43 (74.4%) cases with high Gleason score (>7). Silencing endogenous ADN could promote proliferation and invasion of 22RV1 cells via orchestrating epithelial-to-mesenchymal transition (EMT) process. TGF-beta1, a potent EMT inducer, could decrease levels of chromatin markers associated with active genes (H3K4me3, H4acetylK16), and increase levels of repressive marker (H3K27me3) at ADN promoter in 22RV1 cells. Additionally, 5-aza and TSA treatment restored ADN expression in LNCaP cells in which the ADN expression was almost absent. MSP analysis revealed that methylation in the promoter might be involved in decreased expression of ADN in PCa tissues. CONCLUSION: Our findings indicated that endogenous ADN may function as a tumor suppressor gene through inhibiting EMT of PCa cells but is down-regulated in PCa via promoter hypermethylation.CI - (c) 2015 Wiley Periodicals, Inc.