TRIM29 regulates the SETBP1/SET/PP2A axis via transcription factor VEZF1 to promote progression of ovarian cancer.

Ovarian cancer (OC) is a common gynecological malignant tumor that seriously endangers the health of women worldwide. Tripartite motif containing 29 (TRIM29) is a TRIM family member that is frequently overexpressed in OC. However, the specific role of TRIM29 in OC remains obscure. To investigate the underlying molecular mechanism, a global proteomics analysis identified SET binding protein 1 (SETBP1) as a crucial target of TRIM29. Subsequently, the SETBP1/SET/Protein phosphatase 2 (PP2A) axis was confirmed to be required for the recovery of cancer stem cell (CSC)-like phenotype suppressed by TRIM29 knockdown. Mechanistically, TRIM29 facilitated SETBP1 transcriptional activation via the VEZF1 transcription factor. More importantly, TRIM29 promoted VEZF1 mRNA translation by recruiting RNA binding protein BICC1 to its 3'UTR. The clinical significance was established by the association of TRIM29 and SETBP1 expression with clinicopathological features in OC samples. The SETBP1/SET/PP2A axis driven by TRIM29 via transcription factor VEZF1 is at least one of the primary mechanisms underlying TRIM29 maintenance of the CSC-like characteristics in OC.

TRIM29 alters bioenergetics of pancreatic cancer cells via cooperation of miR-2355-3p and DDX3X recruitment to AK4 transcript.

TRIM29 is dysregulated in pancreatic cancer and implicated in maintenance of stem-cell-like characters of pancreatic cancer cells. However, the exact mechanisms underlying oncogenic function of TRIM29 in pancreatic cancer cells remain largely unclarified. Using a global screening procedure, the current study found that adenylate kinase 4 (AK4) was profoundly reduced by TRIM29 knockdown. In addition, our data demonstrated that TRIM29 knockdown altered bioenergetics and suppressed proliferation and invasion of pancreatic cancer cells via downregulation of AK4 at the posttranscriptional level. The current study demonstrated that upregulation of microRNA-2355-3p (miR-2355-3p) upregulated AK4 expression via facilitating DDX3X recruitment to the AK4 transcript, and TRIM29 knockdown thereby destabilized the AK4 transcript via miR-2355-3p downregulation. Collectively, our study uncovers posttranscriptional stabilization of the AK4 transcript by miR-2355-3p interaction to facilitate DDX3X recruitment. Regulation of AK4 by TRIM29 via miR-2355-3p thereby provides additional information for further identification of attractive targets for therapy with pancreatic cancer.

m6A-YTHDF1-mediated TRIM29 upregulation facilitates the stem cell-like phenotype of cisplatin-resistant ovarian cancer cells.

Ovarian cancer is the deadliest gynaecologic malignancy, and the five-year survival rate of patients is less than 35% worldwide. Cancer stem cells (CSCs) are a population of cells with stem-like characteristics that are thought to cause chemoresistance and recurrence. TRIM29 is aberrantly expressed in various cancers and associated with cancer development and progression. Previous studies showed that the upregulation of TRIM29 expression in pancreatic cancer is related to stem-like characteristics. However, the role of TRIM29 in ovarian cancer is poorly understood. In this study, we found that TRIM29 expression was increased at the translational level in both the cisplatin-resistant ovarian cancer cells and clinical tissues. Increased TRIM29 expression was associated with a poor prognosis of patients with ovarian cancer. In addition, TRIM29 could enhance the CSC-like characteristics of the cisplatin-resistant ovarian cancer cells. Recruitment of YTHDF1 to m6A-modified TRIM29 was involved in promoting TRIM29 translation in the cisplatin-resistant ovarian cancer cells. Knockdown of YTHDF1 suppressed the CSC-like characteristics of the cisplatin-resistant ovarian cancer cells, which could be rescued by ectopic expression of TRIM29. This study suggests TRIM29 may act as an oncogene to promote the CSC-like features of cisplatin-resistant ovarian cancer in an m6A-YTHDF1-dependent manner. Due to the roles of TRIM29 and YTHDF1 in the promotion of CSC-like features, they may become potential therapeutic targets to combat the recurrence of ovarian cancer.

ISG15 suppresses translation of ABCC2 via ISGylation of hnRNPA2B1 and enhances drug sensitivity in cisplatin resistant ovarian cancer cells.

Cisplatin-based chemotherapies have long been considered as a standard chemotherapy in ovarian cancer. However, cisplatin resistance restricts beneficial therapy for patients with ovarian cancer. The ubiquitin-like protein interferon-stimulated gene 15 (ISG15) encodes a 15-kDa protein, that is implicated in the post-translational modification of diverse proteins. In this work, we found that ISG15 was downregulated in cisplatin resistant tissues and cell lines of ovarian cancer. Functional studies demonstrated that overexpression of wild type (WT) ISG15, but not nonISGylatable (Mut) ISG15 increased cell responses to cisplatin in resistant ovarian cancer cells. Furthermore, we found that WT ISG15 decreased ABCC2 expression at the protein level. Importantly, overexpression of ABCC2 blocked sensitizing effect of ISG15 on cisplatin. In addition, we identified that hnRNPA2B1 was recruited to 5'UTR of ABCC2 mRNA and promoted its translation, which was blocked by ISG15. We further demonstrated that hnRNPA2B1 could be ISGylated, and ISGylation blocked its recruitment to ABCC2 mRNA, thereby suppressed translation of ABCC2. Altogether, our data support targeting ISG15 might be a potential therapeutic strategy for patients with cisplatin-resistant ovarian cancer.

Loss of TRIM29 suppresses cancer stem cell-like characteristics of PDACs via accelerating ISG15 degradation.

TRIM family proteins are defined as E3 ubiquitin ligases because of their RING-finger domains. The ubiquitin-like protein interferon-stimulated gene 15 (ISG15) encodes a 15-kDa protein, that is implicated in the posttranslational modification of diverse proteins. Both TRIM29 and ISG15 play both pro-tumoral and anti-tumoral functions in cancer cells derived from different histology. In the current study, we demonstrated that correlation expression of TRIM29 and ISG15 in pancreatic ductal adenocarcinomas (PDACs). The current study demonstrated that TRIM29 knockdown destabilized ISG15 protein via promoting its processing by calpain 3 (CAPN3). Importantly, the current study found that TRIM29 knockdown suppressed cancer stem cell-like features of PDACs, which can be rescued by ISG15 independent of its conjugation function. In addition, the current study demonstrated that extracellular free ISG15 played an important role in maintenance of cancer stem cell-like features of PDACs. Thereby, the current study displayed a novel mechanism by which TRIM29 modulates ISG15 stability via CAPN3-mediated processing, and subsequently extracellular ISG15 maintains the cancer stem cell-like features of PDAC via autocrine mode of action.

The relationship between baseline exhaled nitric oxide levels and acute mountain sickness.

BACKGROUND: Acute mountain sickness (AMS) is a common disabling condition observed in people ascending to high altitudes. However, a simple predictive test for AMS is not known. The aim of this study was to assess the relationship between baseline exhaled nitric oxide (FENO) and AMS occurrence. METHODS: Eighty healthy lowland Chinese adults were recruited for this study. FENO was measured at baseline, as well as 6 and 24 hours after arrival in Tibet. The standard Lake Louise Score (LLS) consensus symptoms questionnaire was used to assess the incidence and severity of AMS. RESULTS: Individuals with a high LLS (> 3) had higher FENO levels at baseline and after arrival in Tibet than people with a low LLS (≤ 3) (baseline: 22.9 ± 11.9 versus 16.7 ± 6.4; 6 hours: 26.2 ± 16.7 versus 17.9 ± 5.7; 24 hours: 24.9 ± 13.1 versus 16.3 ± 1.7; all P < 0.01). Evaluation of risk factors revealed that female gender, diabetes and not smoking were associated with a high AMS score (all P < 0.05), but that hypertension showed no association (P > 0.05). CONCLUSIONS: This prospective observational study suggests that baseline FENO levels may be positively correlated with AMS in healthy Chinese lowlanders.

Effect of malignant tumor on neuromuscular block of cisatracurium / 中华麻醉学杂志

Objective To investigate the effect of malignant tumor on neuromuscular block of cisatracurium. Methods Sixty ASA Ⅰ or Ⅱ patients with head and neck neoplasms (15 cases with benign tumor, 45 with malignant tumor), aged 18-64 yr, were randomly divided into 4 groups ( n = 15 each): Ⅰ benign tumor group (group B,3 × ED95 ); Ⅱ -Ⅳ different dose cisatracurium group (group C1 (2 × ED95 ), C2 (3 × ED95 ) and C3 (4 ×ED95)). Neuromuscular block was assessed with accelerograph F (TOF-watch SX). Single stimulation of ulnar nerve was used. Anesthesia was induced with TCI of propofol (target plasma concentration 3 μg/ml) and remifentanil (target effect-site concentration 3 ng/ml). Tracheal intubation was facilitated with cisatracurium 0.15 mg/kg in group B, and with cisatracurium 0.10, 0.15 and 0.20 mg/kg in group C1, C2 and C3 respectively. The onset time, clinical duration, time for recovery of T/Tc to 75 % and recovery index were recorded. Results The clinical duration, time for recovery of T/Tc to 75 % and recovery index were significantly longer in group C2 than in group B (P ＜ 0.05). The onset time was significantly shorter, while the clinical duration and time for recovery of T/Tc to 75% were significantly longer in group C2 and C3 than in group C1 , and in group C3 than in group C2 ( P ＜0.05) .Conclusion The duration of action and recovery times of cisatracurium were prolonged in patients with malignant tumor.

[The effect of telomerase reverse transcriptase on 5-HT induced pulmonary artery smooth muscle cells proliferation].

OBJECTIVE: To investigate the effect of telomerase reverse transcriptase (TERT) to the proliferation of 5-HT induced pulmonary artery smooth muscle cells (PASMCs). METHODS: The PASMCs proliferation experiment was performed to detect the effort on PASMCs of 5-HT or ASODN TERT (antisense oligoribonucleotides TERT designed according to the rat TERT mRNA sequence of gene bank). The immunohistochemistry staining experiment and the in situ hybridization experiment were to detect the TERT protein and mRNA expression with 5-HT or ASODN TERT. FITC marked ASODN TERT experiment was done to research the distribution of ASODN TERT in PASMCs. RESULTS: 5-HT promoted PASMCs proliferation in a dose-dependent manner (10(-9) - 10(-5) mol/L). 5-HT also significantly increased TERT expression at protein and mRNA levels as shown by immunohistochemistry staining and the in situ hybridization studies. This effect could be blocked by ASODN TERT in a time and dose-dependent manner. CONCLUSIONS: Our experiments show TERT is one of the key factors in the procession of 5-HT induced PASMCs proliferation. ASODN TERT might be a potential therapy agent for pulmonary hypertension.