SHCBP1 regulates STAT3/c-Myc signaling activation to promote tumor progression in penile cancer.

A challenge in developing novel strategies for penile cancer (PC) is the limited understanding of the regulatory mechanisms involved in PC development. This study aims to examine the expression of SHC SH2 Domain-Binding Protein 1 (SHCBP1) in PC and to explore its oncogenic function. Aberrant SHCBP1 expression was observed in PC tissues compared with normal penile tissues. SHCBP1 expression was significantly associated with the pathological grade, T stage, nodal status, and pelvic lymph node metastasis, and could serve as an independent factor for unfavorable overall survival in PC. Manipulation of SHCBP1 expression affected cell proliferation, soft agar clonogenesis, and cell migration and invasion in PC cell lines. Moreover, we identified STAT3/c-Myc signaling as a potential downstream target of SHCBP1. SHCBP1 interacted with JAK2 and STAT3 upon EGF stimulation, which might regulate STAT3/c-Myc signaling activation in PC cells. Disruption of STAT3/c-Myc signaling attenuated cell proliferation and cell migration/invasion in PC cell lines. Nevertheless, overexpression of constitutively activated STAT3 or c-Myc rescued cell proliferation and cell migration/invasion caused by SHCBP1 depletion in PC cell lines. Consistently, SHCBP1 depletion attenuated STAT3/c-Myc signaling and suppressed tumor growth in a murine xenograft model. Importantly, correlated expression of SHCBP1, p-STAT3, and c-Myc was observed in PC tissues, confirming the clinical relevance of SHCBP1/STAT3/c-Myc signaling in PC. In conclusion, aberrant SHCBP1 expression could serve as a potential prognostic biomarker for PC. SHCBP1 might activate the STAT3/c-Myc signaling pathway to promote tumor progression in PC, which may serve as a potential target for PC treatment.

Dysuria due to benign prostatic hyperplasia of the median lobe with ketamine-associated uropathy in a young male.

BACKGROUND: Benign prostatic hyperplasia (BPH) rarely occurs in children or young males. In this case report, a 29-year-old male patient diagnosed with BPH coexisting with ketamine-associated uropathy was reported to investigate the possible relationship between BPH and ketamine-associated uropathy as well as therapeutic strategies. CASE PRESENTATION: A 29-year-old male patient with a 3-year history of ketamine inhalation, complaining of dysuria with frequency and urgency, was admitted. Hydronephrosis, hydroureters, uneven bladder wall thickening and a tumour located in the outlet of the bladder were detected with computed tomography (CT). The patient agreed to cystoscopy under general anaesthesia. A spherical tumour with a diameter of approximately 2 cm was found to originate from the median lobe of the prostate and follicular lesions were diffusely distributed on the right bladder wall. The tumour and follicular lesions in the bladder were resected successfully, and pathology demonstrated BPH and chronic inflammation of the mucous membranes separately. The patient quit ketamine completely during the one-year follow-up. Dysuria was relieved completely and no tumour or follicular neoplasm recurrence was found. CONTRIBUTION: Inflammation in the urothelium, as a direct or indirect consequence of ketamine, may contribute to the development of BPH. Both surgical interventions to remove obstruction and ketamine cessation are necessary approaches.

Molecular features of pleomorphic xanthoastrocytoma.

Pleomorphic xanthoastrocytoma (PXA) is a rare central nervous system tumor occurring mostly in children and young adults. Next-generation sequencing of 295 cancer-related genes was used to investigate the molecular profiles of 13 cases of PXA. We found that BRAF V600E (5/13; 38%), FANCA/D2/I/M (5/13; 38%), PRKDC (4/13; 31%), NF1 (3/13; 23%), and NOTCH2/3/4 (3/13; 23%) alterations were the most frequent somatic gene mutations. However, neither PTEN nor EGFR mutation, which is frequently present in glioblastoma, was detected. The KRAS mutation in PXA is reported for the first time in these tumors. Microsatellite stability was present in all cases. Because mutations of FANCA and BRAF and copy number variations of CDKN2A/B are more frequent in PXA than in glioblastoma, they might be used to distinguish the 2 tumors. The MAPK pathway is involved in the pathogenesis of PXA and may be an effective target for treatment.

Silica-induced TNF-alpha and TGF-beta1 expression in RAW264.7 cells are dependent on Src-ERK/AP-1 pathways.

The cytokines secreted by lung macrophages have been shown to play a critical role in the pathogenesis of silicosis, tumor necrosis factor-alpha (TNF-alpha), and transforming growth factor-beta1 (TGF-beta1) are prominent cytokines in silicosis, but the underlying mechanism remains to be determined. The aim of the present study was to investigate the roles of Src-mitogen-activated protein kinase (MAPKs)/activator protein-1 (AP-1) signaling pathways in silica-induced TNF-alpha and TGF-beta1 expression in macrophage cells (RAW264.7). It was found that silica activated Src, p38 kinase, and extracellular signal-regulated kinase (ERK) in RAW264.7 cells. The induction of TNF-alpha and TGF-beta1 by silica was suppressed by Src inhibitor (PP1), ERK inhibitor (PD98059), but not by p38 kinase inhibitor (SB203580). Dominant negative mutant c-Jun (TAM67) inhibited silica-induced AP-1 DNA binding activity and downregulated the TNF-alpha and TGF-beta1 expression. In addition, PD98059 but not SB203580 inhibited the AP-1 DNA binding activity induced by silica. Based on these findings, it was conclude that Src-ERK/AP-1 signaling pathways are involved in the TNF-alpha and TGF-beta1 expression induced by silica in macrophages.

Identification of differentially expressed genes in rat silicosis model by suppression subtractive hybridization analysis.

The critical molecular mechanism in the development of the pulmonary fibrosis remains unknown, leaving diagnosed patients with a poor prognosis. To isolate the genes specifically up-regulated in pulmonary fibrosis, we established a rat silicosis model 360 d after treatment with crystalline silica suspension. Radiographs of chests showed that some scattered high-density shadows appeared in the lung field. Typical microscopic fibrosing silicotic nodules formed in the lung, alveolar epithelial cells and bronchial epithelial cells, particularly around the partial fibrosing silicotic nodules; some of them showed atypical hyperplasia that suggested a correlation between silicosis and lung cancer. Suppression subtractive hybridization analysis was performed to compare gene expression in lung tissue with silicosis and normal lung tissue. Reverse transcription-polymerase chain reaction showed that the expressions of seven novel cDNA sequences identified by suppression subtractive hybridization in lung tissue with silicosis differed from normal lung tissue. Bioinformatics analysis showed that 47 positive clones represented 35 genes containing two putative proteins and four predicted similar proteins. The analysis also showed that some screened genes in silicosis, such as prolyl 4-hydroxylases, actin-related protein-2/3 complex and acidic mammalian chitinase, have not been previously reported. These genes may provide new clues for investigating the molecular mechanisms in the development of pulmonary fibrosis.

Role of extracellular signal-regulated kinase, p38 kinase, and activator protein-1 in transforming growth factor-beta1-induced alpha smooth muscle actin expression in human fetal lung fibroblasts in vitro.

Myofibroblasts characterized by alpha smooth muscle actin(alpha-SMA) expression play a key role in pulmonary fibrosis. Transforming growth factor-beta1 (TGF-beta1) is likely to be involved in the emergence of myofibroblasts, but the intracellular signal pathways for this process have not been well determined. The aim of the present study was to investigate the role of mitogen-activated protein kinase (MAPK)/activator protein-1 (AP-1) signaling pathways in TGF-beta1-induced alpha-SMA expression in human fetal lung fibroblasts (HLF-02). We found that TGF-beta1 treatment activated p38 kinase and extracellular signal-regulated kinase (Erk) in HLF-02 cells. The induction of alpha-SMA by TGF-beta1 was suppressed by p38 kinase inhibitor (SB203580) and Erk inhibitor (PD98059). AP-1 inhibitor curcumin also inhibited TGF-beta1-induced alpha-SMA expression. In addition, dominant negative mutant c-Jun (TAM67) downregulated TGF-beta1-induced AP-1 transactivation and alpha-SMA expression. In additional, PD98059 but not SB203580 inhibited the AP-1 DNA binding activity induced by TGF-beta1. Based on these findings, we conclude that p38 kinase, Erk, and AP-1 are responsible for the alpha-SMA expression induced by TGF-beta1 in human fetal lung fibroblasts. Erk is involved in inducing alpha-SMA expression via AP-1 activation.

[Sudy on the activation of early growth response factor-1 by silica dioxide and its signal pathway].

OBJECTIVE: To discuss the role of early growth response factor (Egr)-1 and it's upstream signaling pathway in the development of silicosis. METHODS: The expression and localization of Egr-1 were analyzed by immunofluorescence and in-situ hybridization. The activity of Egr-1 was observed in treated cells by using a reporter plasmid and EMSA, the activity of ERK1/2 in RAW264.7 incubated with SiO(2) by using a kinase assay, and further by using a kinase inhibitor assay to investigate the role of upstream kinase in the signal pathway of the activation of Egr-1. RESULTS: The obvious increase of expression and transcription of Egr-1 was observed shortly after being treated by silica and its activity increased abruptly. There was an increase of the activity of ERK1/2 in RAW264.7 cells treated, which reached a peak at 30 minutes. The expression and transcription of Egr-1 decreased maniferstly after using kinase inhibitors. CONCLUSION: Egr-1 expression can be induced by silica dioxide in RAW264.7 cells, and the ERK1/2, p38 kinases may take part in this process which suggest the pathway of SiO(2), ERK1/2, p38 and Egr-1 may play an important role in the development of silicosis.