No abstract

A progressive loss of cartilage matrix leads to the development of osteoarthritis (OA). Matrix homeostasis is disturbed in OA cartilage as the result of reduced production of cartilage-specific matrix and increased secretion of catabolic mediators by chondrocytes. Chondrocyte senescence is a crucial cellular event contributing to such imbalance in matrix metabolism during OA development. Here, we identify miR-204 as a markedly up-regulated microRNA in OA cartilage. miR-204 is induced by transcription factors GATA4 and NF-κB in response to senescence signals. Up-regulated miR-204 simultaneously targets multiple components of the sulfated proteoglycan (PG) biosynthesis pathway, effectively shutting down PG anabolism. Ectopic expression of miR-204 in joints triggers spontaneous cartilage loss and OA development, whereas miR-204 inhibition ameliorates experimental OA, with concomitant recovery of PG synthesis and suppression of inflammatory senescence-associated secretory phenotype (SASP) factors in cartilage. Collectively, we unravel a stress-activated senescence pathway that underlies disrupted matrix homeostasis in OA cartilage.

The tumor suppressor p53 is a key prognostic factor in hepatocellular carcinoma (HCC), yet only 35% of grade III tumors exhibit mutation of p53. Several other pathways have been implicated in HCC and, among these, the role of the Notch1/Snail pathway remains unclear. Therefore, we investigated the expression of p53, Notch1, and Snail proteins in HCC with regard to both clinical grade and p53 mutational status. Immunoblotting for p53 revealed that, whereas in many tumors increased p53 was a result of p53 mutation, wildtype p53 (p53WT) expression was also frequently elevated in HCCs. Coordinated evaluation of p53, Notch1, and Snail expression suggests that grade III HCC can be subdivided based on the expression of these three proteins. We found that Notch1 expression in HCC tissues and cell lines is differentially affected by p53WT and mutant p53 (p53Mut). Notch1 expression was correlated with p53 expression in cells expressing p53WT, but was not elevated in p53Mut‐expressing cells. Virally mediated expression or silencing of p53WT or p53Mut confirmed that p53WT overexpression causes Notch1 up‐regulation in HCC. Surprisingly, the consequence of Notch1 overexpression for the proliferative and invasive capacity of HCC cells depends on both the p53 mutational status and activation of the Snail pathway. Conclusion: In the presence of p53WT, Snail/Notch1 activation increased the invasiveness of HCC cells. In contrast, in the absence of p53WT, Notch1 decreased the invasiveness of HCC. Taken together, these findings shed new light on the complex role of the Notch1/Snail axis in HCC and provide a framework for further classifying HCC based on the expression and mutational status of p53 and the expression of Notch1 and Snail. (HEPATOLOGY 2011;53:1352‐1362)

Chondrosarcomas, malignant cartilaginous neoplasms, are capable of transitioning to highly aggressive, metastatic, and treatment-refractory states, resulting in significant patient mortality. Here, we aim to uncover the transcriptional program directing such tumor progression in chondrosarcomas. We conduct weighted correlation network analysis to extract a characteristic gene module underlying chondrosarcoma malignancy. Hypoxia-inducible factor-2α (HIF-2α, encoded by EPAS1) is identified as an upstream regulator that governs the malignancy gene module. HIF-2α is upregulated in high-grade chondrosarcoma biopsies and EPAS1 gene amplification is associated with poor prognosis in chondrosarcoma patients. Using tumor xenograft mouse models, we demonstrate that HIF-2α confers chondrosarcomas the capacities required for tumor growth, local invasion, and metastasis. Meanwhile, pharmacological inhibition of HIF-2α, in conjunction with the chemotherapy agents, synergistically enhances chondrosarcoma cell apoptosis and abolishes malignant signatures of chondrosarcoma in mice. We expect that our insights into the pathogenesis of chondrosarcoma will provide guidelines for the development of molecular targeted therapeutics for chondrosarcoma.