Abstract We aimed to investigate the expression and clinic significance of Rac GTPase Activating Protein 1 (RACGAP1) in human lung adenocarcinoma (LUAD). Online database analysis revealed a significant increase in RACGAP1 mRNA expression among 26 types of tumor tissues, including LUAD tissues. Online database and tissue microarray analyses indicated that RACGAP1 expression was significantly upregulated in LUAD tissues. Genetic variation analysis identified four different genetic variations of RACGAPs in LUAD. Moreover, online database analysis showed that RACGAP1 upregulation was correlated with shorter survival in patients with LUAD. After silencing RACGAP1 expression in A549 cells using siRNA and assessing its protein levels via Western blotting, we found that RACGAP1 knockdown inhibited cell growth and induced apoptosis determined using the Cell Counting Kit-8 assay, colony formation assay, and flow cytometry. Mechanistically, western blot analysis indicated that Bax expression increased, whereas Bcl-2 expression decreased. Moreover, RACGAP1 knockdown attenuated PI3K/AKT pathway activation in lung cancer cells. Taken together, our findings showed that RACGAP1 was overexpressed in LUAD tissues and played an important role in lung cancer by increasing cell growth through the PI3K/AKT signaling pathway. This study suggests recommends evaluating RACGAP1 in clinical settings as a novel biomarker and potential therapeutic target for lung cancer.
Ovarian cancer (OCa) peritoneal metastasis is the leading cause of cancer–related deaths in women with limited therapeutic options available for treating it and poor prognosis, as the underlying mechanism is not fully understood. The clinicopathological correlation of G9a expression was assessed in tumor specimens of ovarian cancer patients. Knockdown or overexpression of G9a in ovarian cancer cell lines was analysed with regard to its effect on adhesion, migration, invasion and anoikis-resistance. In vivo biological functions of G9a were tested by i.p. xenograft ovarian cancer models. Microarray and quantitative RT-PCR were used to analyze G9a-regulated downstream target genes. We found that the expression of histone methyltransferase G9a was highly correlated with late stage, high grade, and serous-type OCa. Higher G9a expression predicted a shorter survival in ovarian cancer patients. Furthermore, G9a expression was higher in metastatic lesions compared with their corresponding ovarian primary tumors. Knockdown of G9a expression suppressed prometastatic cellular activities including adhesion, migration, invasion and anoikis-resistance of ovarian cancer cell lines, while G9a over-expression promoted these cellular properties. G9a depletion significantly attenuated the development of ascites and tumor nodules in a peritoneal dissemination model. Importantly, microarray and quantitative RT-PCR analysis revealed that G9a regulates a cohort of tumor suppressor genes including CDH1, DUSP5, SPRY4, and PPP1R15A in ovarian cancer. Expression of these genes was also inversely correlated with G9a expression in OCa specimens. We propose that G9a contributes to multiple steps of ovarian cancer metastasis and represents a novel target to combat this deadly disease.
Abstract Microprocessor is an essential nuclear complex responsible for the initial RNase-mediated cleavage of primary miRNA, which is a tightly controlled maturation process that requires the proper assembly of Drosha and DGCR8. Unlike previously identified mechanisms directly targeting the enzymatic subunit Drosha, current knowledge about the biological ways of controlling miRNA nuclear maturation through DGCR8 is less addressed. In this study, we unveiled that the microprocessor assembly is governed by a master gene regulator HIF-1α irrespective of its canonical transcriptional activity. First, a widespread protein binding of HIF-1α with DGCR8 instead of Drosha was observed in response to biological stimulations. Similar protein interactions between their corresponding orthologues in model organisms were also observed. After dissecting the essential protein domains, we noticed that HIF-1α suppresses microprocessor assembly via binding to DGCR8. Furthermore, our results showed that HIF-1α hijacks monomeric DGCR8 thus reducing its dimer formation prior to microprocessor assembly, and consequently, the suppressed microprocessor formation and nuclear processing of primary miRNA were demonstrated. In conclusion, here we unveiled the mechanism of how microprocessor assembly is regulated by HIF-1α, which not only demonstrates a non-transcriptional function of nuclear HIF-1α but also provides new molecular insights into the regulation of microprocessor assembly through DGCR8.
Hematopoietic stem cell transplantation (HSCT) and chemotherapy are considered potentially curative options for post-remission therapy in acute myeloid leukemia (AML). However, the comparative effectiveness of these approaches in favorable- and intermediate-risk AML remains unclear and requires further investigation. In this retrospective study, 111 patients diagnosed with de novo favorable- and intermediate-risk AML, categorized according to the ELN 2022 guidelines, were investigated to compare outcomes following autologous HSCT (auto-HSCT), matched sibling donor HSCT (MSD-HSCT), and chemotherapy. Through propensity score matching for disease status before HSCT, 42 cases in first complete remission were selected for each of the auto-HSCT group and the MSD-HSCT group. Additionally, 27 cases in the chemotherapy group, excluding patients with early relapse or death, were included for comparison. In the overall population, the 3-year overall survival (OS) rates were 85.7%, 83.1%, and 70.4% (p = 0.043), while the disease-free survival (DFS) rates were 78.6%, 83.2%, and 57.1% (p = 0.002) in the auto-HSCT, MSD-HSCT, and chemotherapy groups, respectively. Notably, both auto-HSCT and MSD-HSCT demonstrated significantly improved DFS compared to chemotherapy in patients with favorable-risk AML. Multivariate analysis further revealed that chemotherapy was significantly associated with inferior DFS compared to auto-HSCT (HR=2.82; 95% CI, 1.26-6.32, p=0.012), while DFS was similar between the MSD-HSCT and auto-HSCT groups (HR=0.80; 95% CI, 0.31-2.09, p=0.645). The findings suggested the advantages of both MSD-HSCT and auto-HSCT over chemotherapy as post-remission therapy for AML patients with favorable and intermediate risk. Further research is needed to support these conclusions.
Metalloproteins play essential roles in various biological processes ranging from reaction catalysis to free radical scavenging, and they are also pertinent to numerous pathologies including cancer, HIV infection,and inflammation.
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