Context Prolactinomas are the most common functional pituitary adenomas; the aggressive tumors still present challenge to clinicians. Aberrant expression of miRNAs has been functionally associated with prolactinomas. Objective Here we explored the role of miR-137 on the proliferation, invasion, and apoptosis of prolactinomas and its possible mechanism. Results Low expression of miR-137 was correlated with the invasive behavior of human prolactinomas and predicted high recurrence. MiR-137 inhibited cell proliferation, invasion, and survivals of MMQ and GH3 cells and reduced tumor volume in F344 rat prolactinomas. The luciferase reporter assay confirmed that microphthalmia-associated transcription factor (MITF) was the direct target of miR-137. In addition, miR-137 mimics could inhibit MITF expression in vivo and in vitro. Upregulation of MITF expression promoted cell proliferation, invasion, and survivals and reversed the antitumor effect of miR-137 in vivo and in vitro. Furthermore, miR-137 could also upregulate wnt-inhibitory factor-1 and inhibit nuclear translocation of β-catenin. Upregulation of wnt-inhibitory factor-1 with decitabine can enhance the inhibition on cell proliferation of miR-137. A glycogen synthase kinase-3 inhibitor, SB 216763, promoted cell proliferation by upregulation of total/cytoplasmic/nuclear β-catenin and reversed tumor suppression of miR-137 mimics. Conclusions Our data suggest that miR-137 possesses a tumor invasive suppressor function with a prognostic value in prolactinomas by targeting MITF and modulating Wnt-β-catenin signaling pathway.
A polysaccharide from Cordyceps sinensis (NCSP) was reported to attenuate intestinal injury and regulate balance of T helper (Th)1/Th2 cells in immunosuppressed mice. However, whether it influences Th17 and regulatory...
Background Recently, a hotspot mutation in prolactinoma was observed in splicing factor 3b subunit 1 (SF3B1R625H), but its functional effects and underlying molecular mechanisms remain largely unexplored. Methods Using the CRISPR/Cas9 genome editing system and rat pituitary GH3 cells, we generated heterozygous Sf3b1R625H mutant cells. Sanger and whole-genome sequencing were conducted to verify the introduction of this mutation. Transcriptome analysis was performed in SF3B1-wild-type versus mutant human prolactinoma samples and GH3 cells. RT-PCR and minigene reporter assays were conducted to verify aberrant splicing. The functional consequences of SF3B1R625H were evaluated in vitro and in vivo. Critical makers of epithelial-mesenchymal transition and key components were detected using western blot, immunohistochemistry, and immunofluorescence. Suppressing proteins was achieved using siRNA. Results Transcriptomic analysis of prolactinomas and heterozygous mutant cells revealed that the SF3B1R625H allele led to different alterations in splicing properties, affecting different genes in different species. SF3B1R625H promoted aberrant splicing and DLG1 suppression in both rat cells and human tumors. In addition, SF3B1R625H and knocking down DLG1 promoted cell migration, invasion, and epithelial-mesenchymal transition through PI3K/Akt pathway. Conclusions Our findings elucidate a mechanism through which mutant SF3B1 promotes tumor progression and may provide a potent molecular therapeutic target for prolactinomas with the SF3B1R625H mutation.
Background Pituitary adenomas are one type of intracranial tumor, which can be divided into microadenoma (≤ 1 cm), macroadenoma (> 1 cm), and giant adenoma (≥ 4 cm) according to their diametral sizes. They are benign, typically slow-progressing, whereas the biological behavior of some of them is invasive, which presents a major clinical challenge. Treatment of some pituitary adenomas is still difficult due to drug resistance or multiple relapses, usually after surgery, medication, and radiation. At present, no clear prediction and treatment biomarkers have been found in pituitary adenomas and some of them do not cause clinical symptoms, so patients are often found to be ill through physical examination, and some are even found through autopsy. With the development of research on pituitary adenomas, the immune response has become a hot spot and may serve as a novel disease marker and therapeutic target. The distribution and function of immune cells and their secreted molecules in pituitary adenomas are extremely complex. Researchers found that infiltration of immune cells may have a positive effect on the treatment and prognosis of pituitary adenomas. In this review, we summarized the advance of tumor immunity in pituitary adenomas, revealing the immunity molecules as potential biomarkers as well as therapeutic agents for pituitary adenomas. Conclusion The immune studies related to pituitary adenomas may help us find relevant immune markers. At the same time, the exploration of immunotherapy also provides new options for the treatment of pituitary adenomas.
Context Pituitary adenoma (PA) is a common intracranial tumor. The evidence indicates that the tumor immune microenvironment (TIME) is associated with PA and that the intestinal flora influences other tumors' growth through interacting with the TIME. However, how the intestinal microbial flora contributes to the development of PA through the immune response is unknown. Objective and methods Here we used high-throughput Illumina MiSeq sequencing targeting the V3−V4 region of the 16S ribosomal RNA gene to investigate the intestinal flora of patients with growth hormone-secreting pituitary adenoma (GHPA), nonfunctional pituitary adenoma (NFPA), and healthy controls. We determined their effects on tumor growth and the TIME. Fecal microbiota transplantation (FMT) was performed after adoptive transfer via peripheral blood mononuclear cells to tumor-bearing nude mice, which allowed the study of the immune response. Result We discovered differences in the structures and quantities of intestinal flora between patients with GHPA, patients with NFPA, and healthy controls. After FMT, the intestinal flora of GHPA patients promoted the growth of tumors in mouse models. The number of programmed cell death ligand 1 (PD-L1)-positive cells increased in tumor tissues as well as the extent of infiltration of CD8+ cells. Increased numbers of CD3+CD8+ cells and increased levels of sPD-L1 were detected in peripheral blood. Conclusion These findings indicated that the intestinal flora of patients with GHPA promoted tumor growth and that the immune system may mediate this change.
Non-functioning pituitary adenoma (NFPA) is a very common type of intracranial tumor. Monitoring and predicting the postoperative recurrence of NFPAs is difficult, as these adenomas do not present with serum hormone hypersecretion. Long non-coding RNAs (lncRNAs) and protein-coding genes (PCGs) play critical roles in the development and progression of numerous tumors. However, the complex network of RNA interactions related to the mechanisms underlying the postoperative recurrence of NFPA is still unclear. In the present study, 73 patients with NFPA were investigated using high-throughput sequencing and follow-up investigations. In total, 6 of these patients with recurrence within 1 year after surgery were selected as the fast recurrence group, and 6 patients with recurrence 5 years after surgery were selected as the slow recurrence group. By performing differential expression analysis of the fast recurrence and slow recurrence groups, a set of differentially expressed PCGs and lncRNAs were obtained (t-test, P<0.05). Next, protein-protein interaction coregulatory networks and lncRNA-mRNA coexpression networks were identified. In addition, the hub lncRNA-mRNA modules related to NFPA recurrence were further screened and transcriptome expression markers for NFPA regression were identified (log-rank test, P<0.05). Finally, the ability of the hub and module genes to predict recurrence and progression-free survival in patients with NFPA was evaluated. To confirm the credibility of the bioinformatic analyses, nucleolar protein 6 and LL21NC02-21A1.1 were randomly selected from among the genes with prognostic significance for validation by reverse transcription-quantitative PCR in another set of NFPA samples (n=9). These results may be helpful for evaluating the slow and rapid recurrence of NFPA after surgery and exploring the mechanisms underlying NFPA recurrence. Future effective biomarkers and therapeutic targets may also be revealed.
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