ABSTRACT
Cancer is caused primarily by genomic alterations resulting in deregulation of gene regulatory circuits in key growth, apoptosis, or DNA repair pathways. Multiple genes associated with the initiation and development of tumors are also regulated at the level of mRNA decay, through the recruitment of RNA-binding proteins to AU-rich elements (AREs) located in their 3'-untranslated regions. One of these ARE-binding proteins, tristetraprolin (TTP; encoded by Zfp36), is consistently dysregulated in many human malignancies. Herein, using regulated overexpression or conditional ablation in the context of cutaneous chemical carcinogenesis, we show that TTP represents a critical regulator of skin tumorigenesis. We provide evidence that TTP controlled both tumor-associated inflammation and key oncogenic pathways in neoplastic epidermal cells. We identify Areg as a direct target of TTP in keratinocytes and show that EGFR signaling potentially contributed to exacerbated tumor formation. Finally, single-cell RNA-Seq analysis indicated that ZFP36 was downregulated in human malignant keratinocytes. We conclude that TTP expression by epidermal cells played a major role in the control of skin tumorigenesis.
Subject(s)
Carcinogenesis/metabolism , Keratinocytes/metabolism , Skin Neoplasms/metabolism , Skin/metabolism , Tristetraprolin/metabolism , 3' Untranslated Regions , AU Rich Elements , Animals , Carcinogenesis/genetics , Disease Models, Animal , Down-Regulation , ErbB Receptors/metabolism , Gene Regulatory Networks , Humans , Inflammation/metabolism , Mice, Inbred C57BL , RNA Stability , RNA, Messenger/metabolism , RNA-Binding Proteins/metabolism , Signal Transduction , Skin Neoplasms/geneticsABSTRACT
OBJECTIVE: To research the diagnostic performance of clinical potential bone turnover indexes in rheumatoid arthritis (RA) complicated with osteoporosis (OP). METHODS: This study involved 87 RA patients, 48 with OP, and 39 without OP, and 204 non-RA control patients, including those with systemic lupus erythematosus, ankylosing spondylitis, primary Sjogren's syndrome, systemic sclerosis, and healthy patients. The levels of 25-hydroxyvitamin D [25(OH)D], ß-crosslaps (ß-CROSSL), parathyroid hormone (PTH) were measured by electrochemiluminescence (ECLIA), and the level of bone alkaline phosphatase (BALP) was measured by lectin affinity method. RESULTS: The serum concentration of 25(OH)D in the RA with OP group was significantly lower than the control group (P<0.01), while the levels of ß-CROSSL, BALP in the RA with OP group considerably exceeded those found in the control group (P<0.01). The levels of ß-CROSSL and PTH were significantly higher in RA patients with OP than without OP (P<0.01), while the level of 25(OH)D was statistically lower than without OP (P<0.01). An unconditional logistical regression analysis proved an association with low 25(OH)D and elevated ß-CROSSL in RA with OP, with 25(OH)D demonstrating greatest diagnostic potential according to the ROC curve. CONCLUSION: The significantly reduced levels of 25(OH)D and excessive ß-CROSSL may indicate a high risk of the secondary osteoporosis in RA patients.
Subject(s)
Arthritis, Rheumatoid , Bone and Bones/metabolism , Osteoporosis/complications , Osteoporosis/pathology , Vitamin D/analogs & derivatives , Absorptiometry, Photon , Adult , Aged , Alkaline Phosphatase/metabolism , Arthritis, Rheumatoid/blood , Arthritis, Rheumatoid/diagnosis , Arthritis, Rheumatoid/etiology , Arthritis, Rheumatoid/pathology , Bone Density , Collagen/blood , Female , Humans , Middle Aged , Parathyroid Hormone/blood , Peptide Fragments/blood , ROC Curve , Retrospective Studies , Vitamin D/metabolismABSTRACT
Transarterial chemoembolization (TACE) is the standard treatment for unresectable hepatocellular carcinoma (HCC). Hypoxia-induced angiogenesis by TACE is linked to treatment failure; however, whether the chemotherapeutic damage of TACE to HCC could increase tumor angiogenesis has not been explored. The molecular effects of chemotherapy-damaged HCC cells on the neo-angiogenesis were investigated in vitro and in vivo. The expression of growth differentiation factor 15 (GDF15) was significantly upregulated in HCC cells exposed to chemotherapeutic agents. GDF15 from chemotherapy-damaged HCC cells promoted the in vitro proliferation, migration, and tube formation of endothelial cells. The pro-angiogenic effect of GDF15 was through the activation of Src and its downstream AKT, MAPK, and NF-κB signaling, which was blocked by thalidomide. The use of thalidomide significantly attenuated the in vivo chemotherapy-damaged HCC cells-promoted angiogenesis in nude mice. In conclusion, the chemotherapeutic damage in TACE to HCC could promote tumor angiogenesis via the increased release of GDF15. Thalidomide could reverse these pro-angiogenic effects.