RESUMEN

Ovarian cancer is one of the most common gynaecological malignancies with poor prognosis and lack of effective treatment. The improvement of the situation of ovarian cancer urgently requires the exploration of its molecular mechanism to develop more effective molecular targeted drugs. In this study, the role of human ribosomal protein l35a (RPL35A) in ovarian cancer was explored in vitro and in vivo. Our data identified that RPL35A expression was abnormally elevated in ovarian cancer. Clinically, high expression of RPL35A predicted short survival and poor TNM staging in patients with ovarian cancer. Functionally, RPL35A knock down inhibited ovarian cancer cell proliferation and migration, enhanced apoptosis, while overexpression had the opposite effect. Mechanically, RPL35A promoted the direct binding of transcription factor YY1 to CTCF in ovarian cancer cells. Consistently, RPL35A regulated ovarian cancer progression depending on CTCF in vitro and in vivo. Furthermore, RPL35A affected the proliferation and apoptosis of ovarian cancer cells through PPAR signalling pathway. In conclusion, RPL35A drove ovarian cancer progression by promoting the binding of YY1 and CTCF promoter, and inhibiting this process may be an effective strategy for targeted therapy of this disease.

Asunto(s)

RESUMEN

BACKGROUND: Cholangiocarcinoma (CCA) is a biliary epithelial malignant tumor with an increasing incidence worldwide. Therefore, further understanding of the molecular mechanisms of CCA progression is required to identify new therapeutic targets. METHODS: The expression of RPL35A in CCA and para-carcinoma tissues was detected by immunohistochemical staining. IP-MS combined with Co-IP identified downstream proteins regulated by RPL35A. Western blot and Co-IP of CHX or MG-132 treated CCA cells were used to verify the regulation of HSPA8 protein by RPL35A. Cell experiments and subcutaneous tumorigenesis experiments in nude mice were performed to evaluate the effects of RPL35A and HSPA8 on the proliferation, apoptosis, cell cycle, migration of CCA cells and tumor growth in vivo. RESULTS: RPL35A was significantly upregulated in CCA tissues and cells. RPL35A knockdown inhibited the proliferation and migration of HCCC-9810 and HUCCT1 cells, induced apoptosis, and arrested the cell cycle in G1 phase. HSPA8 was a downstream protein of RPL35A and overexpressed in CCA. RPL35A knockdown impaired HSPA8 protein stability and increased HSPA8 protein ubiquitination levels. RPL35A overexpression promoted CCA cell proliferation and migration. HSPA8 knockdown inhibited CCA cell proliferation and migration, and reversed the promoting effect of RPL35A. Furthermore, RPL35A promoted tumor growth in vivo. In contrast, HSPA8 knockdown suppressed tumor growth, while was able to restore the effects of RPL35A overexpression. CONCLUSION: RPL35A was upregulated in CCA tissues and promoted the progression of CCA by mediating HSPA8 ubiquitination.

Asunto(s)

Asunto(s)

RESUMEN

BACKGROUND: RPL35A has been reported to work as a biomarker in tumor angiogenesis. However, little work has been performed on the expression level and functional importance of RPL35A in gastric cancer (GC). METHODS: The protein expression level of RPL35A was detected by immunohistochemical staining and western blot analysis. The Celigo cell counting assay was used to assess cell proliferation. Both the wound healing assay and the transwell assay were conducted to evaluate cell migration. Flow cytometric analysis was utilized to detect cell apoptosis and cell cycle. A mouse xenograft model was constructed for in vivo experiments. RESULTS: The results demonstrated that RPL35A expression was abundantly up-regulated in GC and positively related to tumor infiltrate. In addition, RPL35A knockdown could significantly suppress cell proliferation, migration, enhance apoptosis and arrest cell cycle. The in vivo study also verified the inhibitory effects of RPL35A knockdown on GC tumorigenesis. CONCLUSIONS: The above mentioned results indicated that the knockdown of RPL35A might be a considerable therapeutic strategy for the treatment of gastric cancer.

RESUMEN

BACKGROUND: Diamond-Blackfan anemia is a rare congenital red blood cell aplasia characterized by failed erythropoiesis, congenital abnormalities in up to 50% of patients, growth retardation in up to 30% of patients, and a predisposition to malignancy. Diamond-Blackfan anemia is both clinically and genetically a heterogenous condition ranging from subtle asymptomatic erythroid abnormalities to non-immune hydrops fetalis. Current treatment options include corticosteroid therapy, chronic red blood cell transfusions, and hematopoietic stem cell transplantation with gene therapy receiving recent attention. We report the first documented case of Diamond-Blackfan anemia in a Caucasian girl secondary to a sporadic heterozygous whole gene deletion in RPL35A in South Africa. Limited resources, non-availability of tests, unfamiliarity that comes with rare diseases, an expanded differential diagnosis, and an associated neutropenia led to a delay in the diagnosis of Diamond-Blackfan anemia. This case reminds clinicians of Diamond-Blackfan anemia as a cause of aplastic anemia and highlights the difficulty and obstacles in diagnosing Diamond-Blackfan anemia in resource-limited countries. CASE PRESENTATION: We report a case of a 6-week-old Caucasian girl presenting with urosepsis and heart failure secondary to a severe anemia and neutropenia. Limited experience and resources resulted in a delay in diagnosis. Genetic studies later confirmed a heterozygous whole gene deletion of RPL35A. Initial treatment was directed toward correcting the anemia with red blood cell transfusion every 3 to 5 weeks. CONCLUSION: Diamond-Blackfan anemia is a rare disease that carries significant morbidity and mortality if not diagnosed early and managed appropriately. Limited health resources, patient registries, and specialists as seen in developing countries result in a paucity of knowledge about Diamond-Blackfan anemia in Africa. This case reminds clinicians about Diamond-Blackfan anemia as a cause for anemia in infants, the limitations in making the diagnosis in under-resourced health care systems, and the need for standardized treatment protocols applicable to resource-limited countries.

Asunto(s)

RESUMEN

3q27.2-qter deletion syndromes feature an overlapping set of terminal and interstitial deletions with variable congenital malformations. Diamond-Blackfan anemia (DBA) is etiologically heterogeneous disorder in which one cause is dominant mutations of the RPL35A gene on 3q29. We report a child with a 3q27.2-qter deletion that contains the RPL35A gene. She had clinical and laboratory features consistent with DBA and as well, an unexplained immunodeficiency disorder. Given these unusual findings, we reviewed other patients in the literature with overlapping genomic deletions. In addition, we evaluated our patient for the immunodeficiency disorder, RIDDLE syndrome, due to recessive mutations in the RNF168 gene on 3q29. A PubMed search for case reports of 3q27.2-qter overlapping deletions was performed. To determine if RPL35A was in the deletion region, the chromosomal regions reported were mapped to genomic regions using the UCSC Genome Browser. We identified 85 overlapping deletions, of which six included the RPL35A gene and all should be had DBA. Interestingly, none of the reported cases had immunodeficiency. To evaluate RIDDLE syndrome (radiosensitivity, immunodeficiency, dysmorphic features, and learning difficulties), we sequenced the remaining RNF168 gene and examined her fibroblast culture for a DNA double strand break repair deficiency. These results were normal, indicating that the immunodeficiency is unlikely to result from a RNF168 deficiency. We show that RPL35A haploinsufficiency is a cause of DBA and we report a novel case with 3q27.2-qter deletion and immunodeficiency. The etiology for the immunodeficiency remains unsolved and could be caused by an unknown gene effect or consequent to the DBA phenotype.

Asunto(s)