HCdc14A Expressed In Human Pituitary And Its Mechanism

BackgroundPituitary gland is divided into two parts:the anterior functional adenohypophysis and posterior neurohypophysis. The Adenohypophysis coordinate signals from the hypothalamus and peripheral endocrine organs, and adjust the secretion of peripheral organs endocrine hormone. Pituitary adenoma is a common tumor in neurosurgical patients, derived from adenohypophysis parenchymal cells, accounting for about10%-15%of intracranial tumors. The secretion of abnormal hormone also cause related symptoms.Prolactinoma secretes prolactin, leading to sexual dysfunction and galactorrhea. Thyroid stimulating hormone tumor cause hyperthyroidism. Adrenocorticotropic hormone tumors secrete adrenocorticotropic hormone, resulting in Cushing’s syndrome. Growth hormone tumors secrete growth hormone, resulting in gigantism and acromegaly. Gonadotropin tumor rarely secrete active luteinizing hormone and follicle-stimulating hormone which leading to sexual hyperfunction, and most of gonadotropin tumors with no obvious clinical manifestation is considered to be non-functioning tumors. The other non-functioning tumors do not secrete hormones that can be detected. Pituitary adenoma shows as a benign growth tumor, and about50%of the tumors are found to invade into nearly structures such as dura mater, optic nerve and skull base bone, which is considered to be invasive pituitary adenoma. The mechanism of the occurrence and development of the pituitary adenoma is similar to the other benign tumor. Most of different phenotypes of pituitary adenomas, including hormonal active adenoma and non-functional adenomas, are also considered to be a monoclonal tumor, which is derived from a genetically modified pluripotent stem cells.The mutations of tumor suppressor gene P53are most common in human tumors, and were considered to related to50%cancers. For the half-life is very short, the wild type P53gene in normal tissues is difficult to detect using immunohistochemical methods. But the mutant P53gene product can be easily detected for the longer half-life. The expression of P53is related to the invasiveness of pituitary tumor, and expressed only in invasive tumors, which is considered to be a sign of invasiveness.Cdcl4exists in almost all eukaryotes, encodes a new member family of dual specificity serine/threonine phosphatase. And it is confirmed that Cdc14can reverse Cdk activity, played a key role in mitotic exit protein network in budding yeast cells. There are two human homologues of Cdc14, called hCdc14A, hCdc14B, with50%sequence homology. The abnormal expression of hCdc14A protein levels can lead to abnormal chromosome segregation and cytoplasm division. And the abnormal protein expression is accompanied with abnormal morphology of the cells. hCdc14A can dephosphorylate the Erk3, and also against the phosphorylation of Cdk. It also plays a role in cell proliferation through the stabilize Erk3-cyclinD3complexes. The studies indicated that high Cdc14A expression is not compatible with wild-type p53expression, suggesting that there may be some mechanism in wild-type P53tumor cells, inhibiting hCdc14A high expression in order to protect P53effect, high expression hCdc14A can inhibit the activity of P53, which prevents the cell cycle and apoptosis in abnormal cells.There is no report or literature to describe the expression of hCdc14A in pituitary. In this study, the expression of hCdc14A and P53in the human pituitary tumor were detected by immunohistochemical methods and reveal the relationship between the different pituitary tumor types, tumor invasion, other prognostic indicators, the role of hCdc14A proteins in the pathogenesis of pituitary tumors.MethodsPituitary tumor specimens:Specimens of pituitary adenomas were obtained at the time of trans-sphenoidal surgery from43patients. All the cases were collected during the period of June2012to December2012at the Department of Neurosurgery, second affiliated hospital of Zhejiang University. Clinical data were collected, such as patients age, sex, clinical symptoms, pituitary hormone levels, tumor tissue pathology, imaging data including tumor size and tumor growth, such as whether the saddle outside invasion. Invasive pituitary adenomas criteria:①using a modified Hardy taxonomy: Ⅲ、Ⅳ grade or C, D, E of invasive tumors classified as invasive adenomas;②In preoperative CT and MR imaging, damage to the cavernous sinus, saddle paraneoplastic hypothalamus and other adjacent structures;③Tumor cell invasion of sellar bone, sellar dura confirmed by pathology;④The bottom of the saddle bone and dura mater was damaged, tumor was spreaded into the sphenoid sinus cavity or punch through the inner wall of the cavernous sinus, sinus structures were surrounded by tumor or tumor ingrowth saddle weeks infringe brain tissue.Normal pituitary tissue:Received from Zhejiang University, Department of Anatomy, a total of two cases, excluded endocrine-related disorders.hCdc14A and P53expression levels in pituitary tumors and normal pituitary tissues were detected with immunohistochemistry and western blot. The relationship between the expression of hCdc14A and pituitary tumor types, the hCdc14A and P53were statistical analysis. Result1clinical data:43cases:19males, aged28-73years, mean age was47.6±12.8;24females, age25-68, mean age was47.3±12.4. Functional pituitary tumors:27cases, of which adrenocorticotropic hormone gland (ACTH) tumor5cases, growth hormone (GH) adenomas4cases, follicle stimulating hormone (FSH)1case, prolactin (PRL) adenoma9cases, multiple secretory function adenoma9cases (which ACTH/FSH adenoma1case, FSH/ACTH adenoma1case, GH/FSH adenoma1case, GH/PRL adenoma2cases, PRL/ACTH adenoma2cases, TSH/PRL adenoma1case), no endocrine adenomas in16patients. By Hardy taxonomy Grade Ⅰ (adenoma,<10mm)11cases, Grade Ⅱ (envelope full of large adenomas, diameter>10mm)5cases, Grade Ⅲ (sphenoid or cavernous sinus invasion)17cases, Grade Ⅳ (invasive central nervous system or extracranial metastases) in10cases. According to the classification of invasive,16cases were invasive pituitary adenoma,27cases were noninvasive pituitary adenoma.2hCdc14A adenomas expressed in pituitary:hCdc14A was not expressed in normal pituitary tissue. Pituitary tumor tissue hCdc14A positive cells was significantly higher than normal pituitary tissues (P <0.01).Invasive behavior pituitary tumor cells was significantly higher than normal pituitary cells (P<0.01) or a non-invasive pituitary tumor cells (P<0.01). Between the functional and non-functional pituitary adenomas, hCdc14A positive cells was no statistically significant (P>0.05).3P53expression in pituitary adenomas situation:In these43cases, P53positive expression rate was18.6%(8/43), in the normal pituitary and non-invasive pituitary adenoma tissue, P53positive expression was not found. In the invasive pituitary adenomas, P53positive expression rate was29.6%(8/27). In invasive pituitary adenoma, P53positive expression level was higher than that in the normal pituitary tissue (P<0.01) and noninvasive pituitary adenomas (P<0.01). There was no significant statistical significance Between the P53positive rate of the functional and nonfunctional pituitary adenomas (P>0.05). Weston-Blot indicated that the P53corresponedly positive expressed in the invasive pituitary adenomas with high expression of hCdc14A.ConclusionhCdc14A was not expressed in normal pituitary, highly expressed in pituitary tumors, and its expression was not associated with the functionality, but closely related to tumor aggressiveness, which indicated that hCdc14A takes an important role in pituitary adenomas proliferation. The positive rate of P53expressed in invasive pituitary tumors was confirmed, which had been proved to be an indicator of aggressiveness, and this study suggests that hCdc14A positively correlated with the expression of P53. hCdc14A may play an important role in the development of pituitary tumors through regulate network of P53.