Abstract
BackgroundNonfunctioning pituitary neuroendocrine tumor (NF-PitNET) is difficult to resect. Except for surgery, there is no effective treatment for NF-PitNET. MicroRNA-134 (miR-134) has been reported to inhibit proliferation and invasion ability of tumor cells. Herein, the mechanism underlying the effect of miR-134 on alleviating NF-PitNET tumor cells growth is explored.MethodsMouse pituitary αT3-1 cells were transfected with miR-134 mimics and inhibitor, followed by treatment with stromal cell-derived factor-1α (SDF-1α) in vitro. MiR-134 expression level: we used quantitative real-time PCR (qRT-PCR) to detect the expression of miR-134. Cell behavior level: cell viability and invasion ability were assessed using a cell counting kit-8 (CCK8) assay and Transwell invasion assay respectively. Cytomolecular level: tumor cell proliferation was evaluated by Ki-67 staining; propidium iodide (PI) staining analyzed the effect of miR-134 on cell cycle arrest; western blot analysis and immunofluorescence staining evaluated tumor migration and invasive ability. Additionally, we collected 27 NF-PitNET tumor specimens and related clinical data. The specimens were subjected to qRT-PCR to obtain the relative miR-134 expression level of each specimen; linear regression analysis was used to analyze the miR-134 expression level in tumor specimens and the age of the NF-PitNET population, gender, tumor invasion, prognosis, and other indicators.Results In vitro experiment, miR-134 was observed to significantly inhibit αT3-1 cells proliferation characterized by inhibited cell viability and expressions of vascular endothelial growth factor A (VEGFA) and cell cycle transition from G1 to S phase (P < 0.01). VEGFA was verified as a target of miR-134. Additionally, miR-134-induced inhibition of αT3-1 cell proliferation and invasion was attenuated by SDF-1α and VEGFA overexpression (P < 0.01). In primary NF-PitNET tumor analysis, miR-134 expression level was negatively correlated with tumor invasion (P = 0.003).ConclusionThe regulation of the SDF-1α/miR-134/VEGFA axis represents a novel mechanism in the pathogenesis of NF-PitNETs and may serve as a potential therapeutic target for the treatment of NF-PitNETs.
Highlights
Pituitary tumors are common and account for 10–15% of primary intracranial neoplasms, and 30% originate from gonadotroph [1]
We compared the expression of stromal cell derived factor-1a (SDF-1a) and VEGFA in invasive and non-invasive NF-pituitary neuroendocrine tumor (PitNET) tissue samples, and the results suggested that the expression levels of SDF-1a and VEGFA in invasive NF-PitNET are relatively high (P < 0.0001, Figures 1A, B)
In the analysis of western blot result, we found miR-134 inhibitor + SDF-1a group has the highest expression of VEGFA in aT3-1 cells, followed by miR-134 inhibitor + phosphate buffer saline (PBS) group and blank vector control + SDF-1a group, the lowest is miR-134 mimics + PBS group (P < 0.01, Figure 4A)
Summary
Pituitary tumors are common and account for 10–15% of primary intracranial neoplasms, and 30% originate from gonadotroph [1]. Nonfunctioning pituitary adenomas are usually of gonadotroph origin [2] and cannot secrete biologically active hormones [3]; silent corticotroph, poorly differentiated PIT1-lineage, true null cell tumors, or other silent tumors have been described, and they often have a more aggressive behavior [4]. Patients with NF-PitNET often present with hypopituitarism and visual field defects, due to the compression effect of development of large adenomas [6, 7]. It is urgent to further explore the underlying mechanisms of pituitary tumorigenesis, and provide a theoretical basis for finding new therapeutic targets for NF-PitNET. Nonfunctioning pituitary neuroendocrine tumor (NF-PitNET) is difficult to resect. The mechanism underlying the effect of miR-134 on alleviating NF-PitNET tumor cells growth is explored
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