Dysregulation of the Hippo pathway occurs in a variety of cancers and often correlates with a poor prognosis. To further explore the potential role of Hippo pathway dysregulation in tumor development and progression, we investigated its downstream transcription factor TEAD4 in colorectal cancer (CRC). Increased expression and nuclear localization of TEAD4 were found in a significant portion of CRC tissues, in association with metastasis and a poor prognosis. In CRC cells, TEAD4 knockdown induced the mesenchymal-epithelial transition and decreased cell mobility in vitro and metastasis in vivo. Microarray analysis revealed that TEAD4 promoted cell adhesion and upregulated the epithelial-mesenchymal transition-related transcriptome in CRC cells. Vimentin was identified as a new direct target gene mediating TEAD4 function in CRC cells, whereby forced vimentin expression markedly reversed TEAD4-knockdown-induced cell morphological changes and decreased mobility. Interestingly, rescued expression of both WT TEAD4 and a Y429H mutant can reverse the mesenchymal-epithelial transition and increase vimentin expression, cell mobility and metastatic potential in TEAD4-knockdown CRC cells. The discrepant expression of YAP and TEAD4 in CRC tissues, the rescue ability of TEAD4 mutant defect in YAP binding and no effect on vimentin expression by YAP knockdown in CRC cells, all implicated a YAP-independent manner of TEAD4 function in CRC. Furthermore, vimentin positively correlated and CDH1 reversely correlated with the level of TEAD4 in CRC tissues and xenograft tumors. Our results suggest that TEAD4 nuclear expression can serve as a biomarker for CRC progression and poor prognosis. The transcription factor TEAD4 regulates a pro-metastasis transcription program in a YAP-independent manner in CRC, thus providing a novel mechanism of TEAD4 transcriptional regulation and its oncogenic role in CRC, independently of the Hippo pathway.

Osteonecrosis of the femoral head was induced in rabbits by intramuscular injection of methylprednisolone and vascular occlusion of the capital femoral epiphysis by electrocoagulation. Eight weeks later the animals received no treatment (group A), core decompression by drilling a hole (diameter 1.2 mm) from the outer cortex 2.5 cm distal to the proximal end of the greater trochanter (group B), or injection of 10(7) autologous adipose-derived stem cells (ADSCs) directly into the femoral head (group C). Eight weeks later, microcomputed tomography scans indicated that bone and trabecular volume and density were significantly higher in group C than in other groups. Histology indicated more new bone formation in group C than in other groups. Group C showed strong osteocalcin immunoreactivity in subchondral bone osteoblasts in the necrotic femoral head, whereas few osteocalcin-positive cells were found among osteoblasts in other groups. Thus, autologous ADSC transplantation improved osteogenesis and the microstructure of vascular deprivation-induced osteonecrotic tissue.

The purpose of our study was aimed to determine the functional role of microRNA (miR)-182 in clear cell renal cell carcinoma (ccRCC) and try to clarify its underlying molecular mechanism. Expression of miR-182 in both cancer and peripheral blood samples was analyzed by quantitative real-time PCR (qRT-PCR). Human RCC line Caki-1 cells were transfected with miR-182 mimic, miR-182 inhibitor, or negative controls, and then the cell viability, colony-formation ability, migration, and invasion assay were determined. Luciferase reporter assay, qRT-PCR and Western blotting were used to determine whether insulin-like growth factor 1 receptor (IGF1R) was a target of miR-182. Further, small interfering RNA (siRNA) against IGF1R was co-transfected with miR-182 inhibitor into cells, and then the effects on migration and invasion were assessed. MiR-182 was down-regulated in both cancer and blood samples compared to the matched non-tumor adjacent tissues and healthy volunteers, respectively (both P<0.05). Compared to the control group, cell viability, colony-forming ability, and numbers of migrated and invaded cells were significantly decreased by transfection with miR-182 mimic but were markedly increased by miR-182 inhibitor (all P < 0.05). Luciferase reporter assay confirmed that IGF1R was a target gene of miR-182, and IGF1R was negatively regulated by miR-182. Co-transfection of miR-182 inhibitor with si-IGF1R reversed the effect of miR-182 inhibitor on the migration and invasion of the cells. MiR-182 functions as an anti-oncogene in ccRCC, and miR-182-mediated inhibition of cell migration and invasion might be through directly targeting IGF1R. Key words: MicroRNA-182, clear cell renal cell carcinoma, migration and invasion, insulin-like growth factor 1 receptorRenal cell carcinoma (RCC) is the most common malignant tumor of adult kidney and accounts for approximately 3% of adult cancers with a high mortality at over 40% [1,2]. Clear cell renal cell carcinoma (ccRCC) is the most frequent subtype of RCC accounting for about 75-80% of the tumor [3]. Despite a tremendous advance has been made in available treatments, the prognosis still remains dismal for locally advanced and metastatic RCC [4]. It has been reported that up to 30-40% of patients with RCC present with metastatic disease even after radical resections [5]. Therefore, it is necessary to provide knowledge of molecule mechanisms controlling the metastatic and invasive potential of RCC.MicroRNAs (miRNAs) are a class of small and non-coding RNA molecules that regulate mRNA transcription and translation by base pairing with the 3' untranslated region (UTR) [6]. It has been well demonstrated that miRNAs are involved in the development and progression of various cancers by regulating cell proliferation, invasion, and migration [7,8]. Recently, emerging evidence has suggested the significant roles of miRNAs in RCC [9][10][11]. Among miRNAs, miR-182 was recently found to be associated with the invasive and/or metastatic potential of prostate cancer [12], melanoma [13], an...

While many diseases of aging have been linked to the immunological system, immune metrics with which to identify the most at-risk individuals are lacking. Here, we studied the blood immunome of 1001 individuals age 8-96 and derived an inflammatory clock of aging (iAge), which tracked with multi-morbidity and immunosenescence. In centenarians, iAge was on average, 40 years lower than their corresponding chronological age. The strongest contributor to this metric was the chemokine CXCL9, which was involved in cardiac aging, affected vascular function, and down-regulated Sirtuin-3, a longevity-associated molecule. Thus, our results identify an important link between inflammatory molecules and pathways known to govern lifespan.