Relationship between RSUME and HIF-1α/VEGF-A with invasion of pituitary adenoma

He, Wei; Huang, Ling; Shen, Xiaoli; Yang, Yanlin; Wang, Dapeng; Yang, Yue Wu; Zhu, Xingen

doi:10.1016/j.gene.2016.12.012

Cited by 29 publications

(27 citation statements)

References 32 publications

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“…For patients with somatotroph PitNETs, various prognostic factors have been suggested, including a younger age and higher GH values at diagnosis, tumour hyperintensity signal in T2weighted magnetic resonance imaging, somatostatin receptor expression, higher Ki-67 expression and the tumour cytokeratin pattern [5][6][7][8]. Recent studies suggested that neoangiogenesis and the tumour immune microenvironment play a role in determining the prognosis of neuroendocrine tumours [9][10][11][12][13][14][15]. Tumour-associated macrophages (TAMs), dendritic cells and tumour infiltrating lymphocytes (TILs) are frequently detected in solid tumours, and are involved in the recognition of tumour antigens, in the inflammatory response to tumour cells and in chemotaxis [16].…”

Section: Introductionmentioning

confidence: 99%

Tumour-infiltrating cytotoxic T lymphocytes in somatotroph pituitary neuroendocrine tumours

Iacovazzo

Chiloiro

Carlsen³

et al. 2019

Endocrine

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Introduction Somatotroph pituitary tumours are often resistant to first-generation somatostatin analogues and can invade the surrounding structures, limiting the chances of curative surgery. Recent studies suggested that the immune microenvironment and pro-angiogenic factors can influence neuroendocrine tumour prognosis. In this study, we aimed to investigate the prognostic role of immune cell-specific markers and endocan, a proteoglycan involved in neoangiogenesis and cell adhesion, in a cohort of acromegaly patients who underwent pituitary surgery as first-line treatment. Subjects and methods Sixty four eligible subjects were identified. CD4+, CD8+ and CD68+ cells and endocan expression were evaluated by immunohistochemistry and results correlated with clinical and neuroradiological findings. Responsiveness to somatostatin analogues was assessed in patients with persistent disease following surgery. Results The number of CD8+ lymphocytes was significantly lower in tumours with cavernous sinus invasion (median 0.2/ HPF, IQR: 2.2) compared with those without cavernous sinus invasion (median 2.4/HPF, IQR: 2.3; P = 0.04). Tumours resistant to first-generation somatostatin analogues had lower CD8+ lymphocytes (median 1/HPF, IQR: 2.4) compared with responders (median 2.4/HPF, IQR: 2.9; P = 0.005). CD4+ lymphocytes were observed sporadically. The number of CD68+ macrophages and the endothelial or tumour cell endocan expression did not differ based on tumour size, cavernous sinus invasion or treatment responsiveness. Conclusions Our study suggests that a lower number of CD8+ lymphocytes is associated with cavernous sinus invasion and resistance to treatment with first-generation somatostatin analogues in acromegaly patients. These results highlight a potential role of the tumour immune microenvironment in determining the prognosis of somatotroph pituitary tumours.

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Section: Introductionmentioning

confidence: 99%

Tumour-infiltrating cytotoxic T lymphocytes in somatotroph pituitary neuroendocrine tumours

Iacovazzo

Chiloiro

Carlsen³

et al. 2019

Endocrine

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“…All types of pituitary adenomas exhibit high PTTG levels (Saez et al 1999, Musat et al 2004. Increased RSUME levels in pituitary tumors has also been described (Carbia-Nagashima et al 2007, Shan et al 2012, Gerez et al 2013, He et al 2017. The interplay of these two proteins opens interesting future research avenues for further understanding of pituitary tumor pathogenesis.…”

Section: Discussionmentioning

confidence: 94%

Protein stabilization by RSUME accounts for PTTG pituitary tumor abundance and oncogenicity

Fuertes

Sapochnik

Tedesco

et al. 2018

Endocrine-Related Cancer

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Increased levels of the proto-oncogene pituitary tumor-transforming gene 1 (PTTG) have been repeatedly reported in several human solid tumors, especially in endocrine-related tumors such as pituitary adenomas. Securin PTTG has a critical role in pituitary tumorigenesis. However, the cause of upregulation has not been found yet, despite analyses made at the gene, promoter and mRNA level that show that no mutations, epigenetic modifications or other mechanisms that deregulate its expression may explain its overexpression and action as an oncogene. We describe that high PTTG protein levels are induced by the RWD-containing sumoylation enhancer (RWDD3 or RSUME), a protein originally identified in the same pituitary tumor cell line in which PTTG was also cloned. We demonstrate that PTTG and RSUME have a positive expression correlation in human pituitary adenomas. RSUME increases PTTG protein in pituitary tumor cell lines, prolongs the half-life of PTTG protein and regulates the PTTG induction by estradiol. As a consequence, RSUME enhances PTTG transcription factor and securin activities. PTTG hyperactivity on the cell cycle resulted in recurrent and unequal divisions without cytokinesis, and the consequential appearance of aneuploidies and multinucleated cells in the tumor. RSUME knockdown diminishes securin PTTG and reduces its tumorigenic potential in a xenograft mouse model. Taken together, our findings show that PTTG high protein steady state levels account for PTTG tumor abundance and demonstrate a critical role of RSUME in this process in pituitary tumor cells.

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“…HIF-1α is an important transcription factor in tissues that responds to the hypoxia microenvironment. HIF-1α can let tumor cells adapt to hypoxia microenvironment formed due to the rapid proliferation by regulating various biological processes including glycolysis, angiogenesis factor, vascular endothelial growth factor (VEGF) and 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) (13)(14)(15)(16)(17). Its content can also predict the efficacy of radiotherapy on tumor (18,19).…”

Section: Discussionmentioning

confidence: 99%

Evaluating Changes of Tumor Hypoxia Using 99Tcm-MNLS Hypoxic Imaging

Tian

et al. 2019

Iran J Radiol

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Background: Hypoxia is an important cause of recurrence and metastasis of malignant tumors. Noninvasive detection of the extent of hypoxic areas of tumors is essential for delineation of radiotherapy target areas and dose. Objectives: To investigate the feasibility of 99 Tc m-2-(2-methyl-5-nitro-1H-imidazol-1-yl) ethyl dihydrogen phosphate (99 Tc m-MNLS) hypoxic imaging to monitor the tumor hypoxic state in tumor-bearing mice after radiotherapy. Materials and Methods: Tumor-bearing mice were divided into eight groups: imaged 24 hours before radiotherapy (A24 h before), imaged immediately after radiotherapy (Aimmediately), imaged 24 hours after radiotherapy (A24 h), imaged 48 hours after radiotherapy (A48 h), and the corresponding control groups. Mice in each group received hypoxia imaging at the corresponding time point to calculate the radioactivity ratio of tumor/non-tumor (T/NT). Hypoxia inducible factor-1α (HIF-1α) was determined by immunohistochemistry to investigate the relationship between T/NT ratio and HIF-1α expression in radiotherapy and control groups. Results: T/NT ratio and the expression of HIF-1α in A24 h group were not significantly different from those in A24 h before and control groups, but lower than those in the Aimmediately group and higher than those in the A48 h group. T/NT ratio and the expression of HIF-1α in the A24 h before group had no significant difference compared with those in its control group, while those in the Aimmediately group were remarkably higher than those in its control group. On the other hand, those in A48 h group were lower than those in its control group. There was a positive correlation between T/NT ratio and HIF-1α expression in radiotherapy group and control group at different time points. Conclusion: 99 Tc m-MNLS tumor hypoxic imaging can evaluate the tumor hypoxic status of tumor-bearing mice after radiotherapy.

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Relationship between RSUME and HIF-1α/VEGF-A with invasion of pituitary adenoma

Cited by 29 publications

References 32 publications

Tumour-infiltrating cytotoxic T lymphocytes in somatotroph pituitary neuroendocrine tumours

Tumour-infiltrating cytotoxic T lymphocytes in somatotroph pituitary neuroendocrine tumours

Protein stabilization by RSUME accounts for PTTG pituitary tumor abundance and oncogenicity

Evaluating Changes of Tumor Hypoxia Using 99Tcm-MNLS Hypoxic Imaging

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