Deficiency of BAP1 inhibits neuroblastoma tumorigenesis through destabilization of MYCN.

The transcription factor MYCN is frequently amplified and overexpressed in a variety of cancers including high-risk neuroblastoma (NB) and promotes tumor cell proliferation, survival, and migration. Therefore, MYCN is being pursued as an attractive therapeutic target for selective inhibition of its upstream regulators because MYCN is considered a "undruggable" target. Thus, it is important to explore the upstream regulators for the transcription and post-translational modification of MYCN. Here, we report that BRCA1-associated protein-1 (BAP1) promotes deubiquitination and subsequent stabilization of MYCN by directly binding to MYCN protein. Furthermore, BAP1 knockdown inhibits NB tumor cells growth and migration in vitro and in vivo, which can be rescued partially by ectopic expression of MYCN. Importantly, depletion of BAP1 confers cellular resistance to bromodomain and extraterminal (BET) protein inhibitor JQ1 and Aurora A kinase inhibitor Alisertib. Furthermore, IHC results of NB tissue array confirmed the positive correlation between BAP1 and MYCN protein. Altogether, our work not only uncovers an oncogenic function of BAP1 by stabilizing MYCN, but also reveals a critical mechanism for the post-translational regulation of MYCN in NB. Our findings further indicate that BAP1 could be a potential therapeutic target for MYCN-amplified neuroblastoma.

Durable effect of pyrotinib plus capecitabine in HER-2+ breast cancer patient undergoing peritoneal dialysis: A case report and literature review.

For patients with end-stage renal disease (ESRD), peritoneal dialysis (PD) and hemodialysis (HD) are important renal replacement treatments. Patients on dialysis usually have a high incidence rate of malignant tumors. In 2020, breast cancer has become the malignant tumor with the highest incidence rate in the world. Human epidermal growth factor receptor-2-positive (HER-2+) breast cancer accounts for 20%-30% of the total breast cancer patients. It is highly invasive and has a poor prognosis. Anti-HER-2 treatment is an important therapy for this type of cancer. There are few case reports of anti-HER2-targeted therapy in dialysis patients. We report a 56-year-old Chinese woman with breast cancer (cT3N1MX, Her-2+/HR-). She underwent peritoneal dialysis for 11 years since she had suffered end-stage renal disease. The clinician prescribed the regimen (pyrotinib 320mg qd + capecitabine 1g bid D1-D14 Q3W). The tumor was significantly reduced after 1 month of single administration of pyrotinib, and partially relieved after 2 months of pyrotinib + capecitabine. The main side effects were grade II hand foot syndrome and grade II diarrhea. This case shows that the combination of pyrotinib and capecitabine has potential therapeutic benefits in HER-2+ breast cancer patients with end-stage renal disease.

FIGNL1 is a potential biomarker of cisplatin resistance in non-small cell lung cancer.

BACKGROUND: Fidgetin-like 1 (FIGNL1) participates in tumor resistance by playing the function of homologous recombination repair(HRR). However, the role of FIGNL1 in non-small cell lung cancer (NSCLC) is still unclear. This study aims to understand the expression of FIGNL1 in NSCLC and preliminarily explore its relationship with cisplatin resistance. METHODS: FIGNL1 messenger RNA (mRNA) was analyzed in 1018 NSCLC tissues and 111 adjacent tissues using The Cancer Genome Atlas program. FIGNL1mRNA in cisplatin-resistant and cisplatin-sensitive cell lines was analyzed by the Gene Expression Omnibus project. FIGNL1 protein was detected in 58 NSCLC tissues and 58 adjacent tissues by immunohistochemistry. The relationship between FIGNL1, clinical pathological characteristics and disease-free survival was retrospectively analyzed. Gene ontology was used to analyze the biological process mainly involving FIGNL1, and STRING online constructed its protein interaction network and screened the key genes (hub genes). RESULTS: The Cancer Genome Atlas showed that FIGNL1mRNA was higher in 1018 NSCLC tissues than in 111 adjacent tissues (P < 0.05). In the dataset "GSE157692," FIGNL1mRNA was higher in cisplatin-resistant cell lines (P = 3.80e-05). The hub genes in FIGNL1 and HRR directions are RAD51 and CCDC36. Immunohistochemistry showed that the FIGNL1 protein in 58 NSCLC tissues was higher than that in 58 adjacent tissues (P < 0.01). FIGNL1 is associated with gender, histopathological type, and nerve invasion in NSCLC. The disease-free survival in NSCLC patients with high FIGNL1 expression was shorter (P = 0.032). CONCLUSION: FIGNL1 is associated with poor prognosis in NSCLC, and cisplatin resistance may be involved. These observations provide a clinical basis for exploring FIGNL1 as a potential biomarker for cisplatin resistance in NSCLC.

Association of HER-2/CEP17 Ratio and HER-2 Copy Number With pCR Rate in HER-2-Positive Breast Cancer After Dual-Target Neoadjuvant Therapy With Trastuzumab and Pertuzumab.

Objective: To explore the correlation between HER-2 status and pathological complete response (pCR) in HER-2-positive breast cancer after dual anti-HER-2 neoadjuvant therapy with trastuzumab and pertuzumab. Methods: A total of 57 HER-2-positive breast cancer patients admitted to the Second Affiliated Hospital of Anhui Medical University and Xijing Hospital Affiliated to Air Force Military Medical University, between January 1, 2019 and September 30, 2020, were enrolled in this multicenter retrospective study. HER-2 status, including HER-2/CEP17 ratio and HER-2/cell number ratio, was detected by FISH. The correlation between HER-2 status/clinicopathological data and pCR was analyzed. The ROC curve was drawn to determine the cutoff value. Results: IHC assessment revealed 40 (70.18%) patients with IHC 3+ and 17 (29.82%) with IHC 2+. 41/57 (71.93%) patients achieved pCR. FISH revealed that the ratio of HER-2/chromosome 17 centromere (HER-2/CEP17) (p<0.001) and the ratio of HER-2/cell number (p<0.001) was significantly correlated with the pCR rate. ROC analysis showed that patients with an HER-2/CEP17 ratio ≥4.495 or HER-2/cell number ≥11.650 have a high pCR rate after dual anti-HER-2 neoadjuvant therapy, suggesting its predictive significance. Conclusion: The response to dual-targeted neoadjuvant therapy with trastuzumab and pertuzumab was adequate in hormone receptor-negative, HER-2-positive breast cancer patients. HER-2/CEP17 ratio and HER-2/cell number ratio were crucial for predicting efficacy.

MIF Plays a Key Role in Regulating Tissue-Specific Chondro-Osteogenic Differentiation Fate of Human Cartilage Endplate Stem Cells under Hypoxia.

Degenerative cartilage endplate (CEP) shows decreased chondrification and increased ossification. Cartilage endplate stem cells (CESCs), with the capacity for chondro-osteogenic differentiation, are responsible for CEP restoration. CEP is avascular and hypoxic, while the physiological hypoxia is disrupted in the degenerated CEP. Hypoxia promoted chondrogenesis but inhibited osteogenesis in CESCs. This tissue-specific differentiation fate of CESCs in response to hypoxia was physiologically significant with regard to CEP maintaining chondrification and refusing ossification. MIF, a downstream target of HIF1A, is involved in cartilage and bone metabolisms, although little is known about its regulatory role in differentiation. In CESCs, MIF was identified as a key point through which HIF1A regulated the chondro-osteogenic differentiation. Unexpectedly, unlike the traditionally recognized mode, increased nuclear-expressed MIF under hypoxia was identified to act as a transcriptional regulator by interacting with the promoter of SOX9 and RUNX2. This mode of HIF1A/MIF function may represent a target for CEP degeneration therapy.