He Zhang

Abstract Background Dynamic N 6 -methyladenosine (m 6 A) modification was previously identified as a ubiquitous post-transcriptional regulation that affected mRNA homeostasis. However, the m 6 A-related epitranscriptomic alterations and functions remain elusive in human cancer. Here we aim to identify the profile and outcome of m 6 A-methylation in hepatocellular carcinoma (HCC). Results Using liquid chromatography-tandem mass spectrometry and m 6 A-immunoprecipitation in combination with high-throughput sequencing, we determined the m 6 A-mRNA levels in human HCC. Human HCC exhibited a characteristic gain of m 6 A modification in tandem with an increase of mRNA expression, owing to YTH domain family 2 (YTHDF2) reduction. The latter predicted poor classification and prognosis of HCC patients, and highly correlated with HCC m 6 A landscape. YTHDF2 silenced in human HCC cells or ablated in mouse hepatocytes provoked inflammation, vascular reconstruction and metastatic progression. Mechanistically, YTHDF2 processed the decay of m 6 A-containing interleukin 11 (IL11) and serpin family E member 2 (SERPINE2) mRNAs, which were responsible for the inflammation-mediated malignancy and disruption of vascular normalization. Reciprocally, YTHDF2 transcription succumbed to hypoxia-inducible factor-2α (HIF-2α). Administration of a HIF-2α antagonist (PT2385) restored YTHDF2-programed epigenetic machinery and repressed liver cancer. Conclusion Our results have characterized the m 6 A-mRNA landscape in human HCC and revealed YTHDF2 as a molecular ‘rheostat’ in epitranscriptome and cancer progression.

Author(s): Peng, Hongying; Shi, Junchao; Zhang, Ying; Zhang, He; Liao, Shangying; Li, Wei; Lei, Li; Han, Chunsheng; Ning, Lina; Cao, Yujing; Zhou, Qi; Chen, Qi; Duan, Enkui

Abstract By leveraging tumorgraft (patient-derived xenograft) RNA-sequencing data, we developed an empirical approach, DisHet, to dissect the tumor microenvironment (eTME). We found that 65% of previously defined immune signature genes are not abundantly expressed in renal cell carcinoma (RCC) and identified 610 novel immune/stromal transcripts. Using eTME, genomics, pathology, and medical record data involving >1,000 patients, we established an inflamed pan-RCC subtype (IS) enriched for regulatory T cells, natural killer cells, TH1 cells, neutrophils, macrophages, B cells, and CD8+ T cells. IS is enriched for aggressive RCCs, including BAP1-deficient clear-cell and type 2 papillary tumors. The IS subtype correlated with systemic manifestations of inflammation such as thrombocytosis and anemia, which are enigmatic predictors of poor prognosis. Furthermore, IS was a strong predictor of poor survival. Our analyses suggest that tumor cells drive the stromal immune response. These data provide a missing link between tumor cells, the TME, and systemic factors. Significance: We undertook a novel empirical approach to dissect the renal cell carcinoma TME by leveraging tumorgrafts. The dissection and downstream analyses uncovered missing links between tumor cells, the TME, systemic manifestations of inflammation, and poor prognosis. Cancer Discov; 8(9); 1142–55. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1047

Cancer is a multi-faceted disease comprised of a combination of genetic, epigenetic, metabolic and signalling aberrations which severely disrupt the normal homoeostasis of cell growth and death. Rational developments of highly selective drugs which specifically block only one of the signalling pathways have been associated with limited therapeutic success. Multi-targeted prevention of cancer has emerged as a new paradigm for effective anti-cancer treatment. Platycodin D, a triterpenoid saponin, is one the major active components of the roots of Platycodon grandiflorum and possesses multiple biological and pharmacological properties including, anti-nociceptive, anti-atherosclerosis, antiviral, anti-inflammatory, anti-obesity, immunoregulatory, hepatoprotective and anti-tumour activities. Recently, the anti-cancer activity of platycodin D has been extensively studied. The purpose of this review was to give our perspectives on the current status of platycodin D and discuss its anti-cancer activity and molecular mechanisms which may help the further design and conduct of pre-clinical and clinical trials to develop it successfully into a potential lead drug for oncological therapy. Platycodin D has been shown to fight cancer by inducing apoptosis, cell cycle arrest, and autophagy and inhibiting angiogenesis, invasion and metastasis by targeting multiple signalling pathways which are frequently deregulated in cancers suggesting that this multi-target activity rather than a single effect may play an important role in developing platycodin D into potential anti-cancer drug.

Osteoarthritis (OA) is an urgent public health problem; however, the underlying causal mechanisms remain unclear, especially in terms of inflammatory mediators in cartilage degradation and chondrocyte imbalance. P2X7 receptor (P2X7R) is a critical inflammation switch, but few studies have examined its function and mechanisms in OA‐like pyroptotic inflammation of chondrocytes. In this study, Sprague–Dawley rats were injected in the knee with monosodium iodoacetate (MIA) to induce OA, followed by multiple intra‐articular injections with P2X7R antagonist A740003, P2X7R agonist BzATP, NF‐ κ B inhibitor Bay 11‐7082, and NLRP3 inhibitor CY‐09. Primary rat chondrocytes were harvested and treated similarly. We assessed cell viability, damage, and death via cell viability assay, lactate dehydrogenase (LDH) release, and flow cytometry. Concentrations of adenosine triphosphate (ATP) and interleukin‐ (IL‐) 1 β in cell culture supernatant and joint cavity lavage fluid were analyzed by enzyme‐linked immunosorbent assay. Changes in expression levels of P2X7 and inflammation‐related indicators were analyzed by immunofluorescence, quantitative reverse‐transcription polymerase chain reaction, and western blotting. Cell morphology changes and pyroptosis were observed using transmission electron microscopy. Histology, immunohistochemistry, and microcomputed tomography were used to analyze damage to bone and cartilage tissues and assess the severity of OA. Similar to MIA, BzATP reduced cell viability and collagen II expression in a dose‐dependent manner. Conversely, A740003 ameliorated MIA‐induced cartilage degradation and OA‐like pyroptotic inflammation by rescuing P2X7, MMP13, NF‐ κ B p65, NLRP3, caspase‐1 (TUNEL‐positive and active), and IL‐1 β upregulation. Additionally, A740003 reduced the caspase‐1/propidium iodide double‐positive rate, LDH concentration, and reactive oxygen species production. These effects also occurred via coincubation with Bay 11‐7082 and CY‐09. In conclusion, activated P2X7 promoted extracellular matrix degradation and pyroptotic inflammation in OA chondrocytes through NF‐ κ B/NLRP3 crosstalk, thus, aggravating the symptoms of OA. The study findings suggest P2X7 as a potential target for inflammation treatment, providing new avenues for OA research and therapy.