A new immune signature for survival prediction and immune checkpoint molecules in non-small cell lung cancer.

Background: Immune checkpoint blockade (ICB) therapy has brought remarkable clinical benefits to patients with advanced non-small cell lung carcinoma (NSCLC). However, the prognosis remains largely variable. Methods: The profiles of immune-related genes for patients with NSCLC were extracted from TCGA database, ImmPort dataset, and IMGT/GENE-DB database. Coexpression modules were constructed using WGCNA and 4 modules were identified. The hub genes of the module with the highest correlations with tumor samples were identified. Then integrative bioinformatics analyses were performed to unveil the hub genes participating in tumor progression and cancer-associated immunology of NSCLC. Cox regression and Lasso regression analyses were conducted to screen prognostic signature and to develop a risk model. Results: Functional analysis showed that immune-related hub genes were involved in the migration, activation, response, and cytokine-cytokine receptor interaction of immune cells. Most of the hub genes had a high frequency of gene amplifications. MASP1 and SEMA5A presented the highest mutation rate. The ratio of M2 macrophages and naïve B cells revealed a strong negative association while the ratio of CD8 T cells and activated CD4 memory T cells showed a strong positive association. Resting mast cells predicted superior overall survival. Interactions including protein-protein, lncRNA and transcription factor interactions were analyzed and 9 genes were selected by LASSO regression analysis to construct and verify a prognostic signature. Unsupervised hub genes clustering resulted in 2 distinct NSCLC subgroups. The TIDE score and the drug sensitivity of gemcitabine, cisplatin, docetaxel, erlotinib and paclitaxel were significantly different between the 2 immune-related hub gene subgroups. Conclusions: These findings suggested that our immune-related genes can provide clinical guidance for the diagnosis and prognosis of different immunophenotypes and facilitate the management of immunotherapy in NSCLC.

Follicular cytotoxic CD8 T cells present high cytokine expression, and are more susceptible to Breg-mediated suppression in non-small cell lung cancer.

Tumor-infiltrating CD8 T cells are instrumental to antitumor immunity. In this study, we found that a subset of CXCR5-expressing CD8 T cells, termed follicular cytotoxic T (Tfc) cells, potently infiltrated the untreated tumors from non-small cell lung cancer (NSCLC) patients. On average, Tfc cells represented 14% of total tumor-infiltrating CD8 T cells and 6.6% of total tumor-infiltrating lymphocytes. Upon antigenic stimulation, Tfc cells presented significantly higher degranulation and stronger release of proinflammatory cytokines, including IFNg, IL2, and TNF, and the pleiotropic cytokine IL10 than non-Tfc cells. However, the expression of granzyme B and perforin was significantly lower in Tfc cells than in non-Tfc CD8 T cells. B regulatory (Breg) cells could significantly suppress proinflammatory cytokine production in both Tfc cells and non-Tfc CD8 T cells, but in Tfc cells, a lower concentration was required. Moreover, Breg cells could significantly elevate IL10 expression by Tfc cells but could not affect IL-10 expression by non-Tfc CD8 T cells. The neutralization of IL10 significantly reduced the extent of Breg-mediated regulation. Together, this study demonstrated that Tfc cells represented a significant proportion of tumor-infiltrating CD8 T cells in lung carcinoma. These Tfc cells were different from non-Tfc CD8 T cells in terms of cytokine expression and granzyme and perforin release and were more susceptible to Breg-mediated suppression in an IL-10-dependent manner.

Uterus globulin associated protein 1 (UGRP1) is a potential marker of progression of Graves' disease into hypothyroidism.

Approximately 20% of Graves' disease (GD) patients may result eventually in hypothyroidism in their natural course. Uterus globulin-associated protein 1 (UGRP1) was associated with GD in our previous study. Here we investigated the role of UGRP1 in the development of autoimmune thyroid disease (AITD). The results showed that UGRP1 was expressed in the thyrocytes of most Hashimoto's thyroiditis (HT) patients and a proportion of GD patients (293 HT and 198 GD). The pathologic features of UGRP1-positive thyrocytes resembled "Hürthle cells", and were surrounded by infiltrated leukocytes. The positivity rate of TPOAb in UGRP1-positive GD patients was much higher than that in -negative GD patients. Moreover, UGRP1 was co-expressed with Fas and HLA-DR in the thyrocytes of AITD patients. We also found IL-1ß but not Th1 or Th2 cytokines was able to upregulate the expression of UGRP1. Our findings indicated that UGRP1 may be a novel marker in thyrocytes to predict GD patients who develop hypothyroidism.

SRC1 Deficiency in Hypothalamic Arcuate Nucleus Increases Appetite and Body Weight.

Appetite is tightly controlled by neural and hormonal signals in animals. In general, steroid receptor co-activator 1 (SRC1) enhances steroid hormone signalling in energy balance and serves as a common co-activator of several steroid receptors, such as estrogen and glucocorticoid receptors. However, the key roles of SRC1 in energy balance remain largely unknown. We first confirmed that SRC1 is abundantly expressed in the hypothalamic arcuate nucleus (ARC), which is a critical centre for regulating feeding and energy balance; it is further co-localised with agouti-related protein and proopiomelanocortin neurons in the arcuate nucleus. Interestingly, local SRC1 expression changes with the transition between sufficiency and deficiency of food supply. To identify its direct role in appetite regulation, we repressed SRC1 expression in the hypothalamic ARC using lentivirus shRNA and found that SRC1 deficiency significantly promoted food intake and body weight gain, particularly in mice fed with a high-fat diet. We also found the activation of the AMP-activated protein kinase (AMPK) signalling pathway due to SRC1 deficiency. Thus, our results suggest that SRC1 in the ARC regulates appetite and body weight and that AMPK signalling is involved in this process. We believe that our study results have important implications for recognising the overlapping and integrating effects of several steroid hormones/receptors on accurate appetite regulation in future studies.

Upregulation of bacterial-specific Th1 and Th17 responses that are enriched in CXCR5+CD4+ T cells in non-small cell lung cancer.

The microbial community in the mucosal surfaces is involved in the development of human cancers, including gastric cancer and colorectal cancer. The respiratory tract in the lung also hosts a distinctive microbial community, but the correlation between this community and lung cancer is largely unknown. Here, we examined the Th1 and Th17 responses toward several bacterial antigens, in CD4+ T cells sourced from the peripheral blood (PB), the lung cancer (LC) tissue, and the gastrointestinal (GI) tract of non-small cell lung cancer (NSCLC) patients. Compared to healthy controls, the NSCLC patients presented significantly higher frequencies of Th1 and Th17 cells reacting to Streptococcus salivarius and S. agalactiae, in the PB, LC, and GI tract. Further investigation showed that the upregulation in anti-bacteria response was likely antigen-specific for two reasons. Firstly, the frequencies of Th1 and Th17 cells reacting to Escherichia coli, a typical GI bacterium, were not upregulated in the PB and the LC of NSCLC patients. Secondly, the S. salivarius and S. agalactiae responses could be partially blocked by Tü39, a MHC class II blocking antibody, suggesting that antigen-specific interaction between CD4+ T cells and antigen-presenting cells was required. We also found that S. salivarius and S. agalactiae could potently activate the monocytes to secrete higher levels of interleukin (IL)-6, IL-12, and tumor necrosis factor, which were Th1- and Th17-skewing cytokines. Interestingly, whereas CXCR5+CD4+ T cells represented <20% of total CD4+ T cells, they represented 17%-82% of bacteria-specific Th1 or Th17 cells. Together, these data demonstrated that NSCLC patients presented a significant upregulation of bacterial-specific Th1 and Th17 responses that were enriched in CXCR5+CD4+ T cells.

Function and regulation of LAG3 on CD4+CD25- T cells in non-small cell lung cancer.

LAG3 is a surface molecule found on a subset of immune cells. The precise function of LAG3 appears to be context-dependent. In this study, we investigated the effect of LAG3 on CD4+CD25- T cells from non-small cell lung cancer (NSCLC) patients. We found that in the peripheral blood mononuclear cells of NSCLC patients, LAG3 was significantly increased in CD4+ T cells directly ex vivo and primarily in the CD4+CD25- fraction, which was regulated by prolonged TCR stimulation and the presence of IL-27. TCR stimulation also increased CD25 expression, but not Foxp3 expression, in LAG3-expressing CD4+CD25- cells Compared to LAG3-nonexpressing CD4+CD25- cells, LAG3-expressing CD4+CD25- cells presented significantly higher levels of PD1 and TIM3, two inhibitory receptors best described in exhausted CD8+ T effector cells. LAG3-expressing CD4+CD25- cells also presented impaired proliferation compared with LAG3-nonexpressing CD4+CD25- cells but could be partially rescued by inhibiting both PD1 and TIM3. Interestingly, CD8+ T cells co-incubated with LAG3-expressing CD4+CD25- cells at equal cell numbers demonstrated significantly lower proliferation than CD8+ T cells incubated alone. Co-culture with CD8+ T cell and LAG3-expressing CD4+CD25- T cell also upregulated soluble IL-10 level in the supernatant, of which the concentration was positively correlated with the number of LAG3-expressing CD4+CD25- T cells. In addition, we found that LAG3-expressing CD4+CD25- T cells infiltrated the resected tumors and were present at higher frequencies of in metastases than in primary tumors. Taken together, these data suggest that LAG3-expressing CD4+CD25- T cells represent another regulatory immune cell type with potential to interfere with anti-tumor immunity.

Exposure to particulate matter 2.5 (PM2.5) induced macrophage-dependent inflammation, characterized by increased Th1/Th17 cytokine secretion and cytotoxicity.

Particulate matter PM2.5 is a class of airborne particles and droplets with sustained high levels in many developing countries. Epidemiological studies have shown the association between sustained high level of PM2.5 and the risk of many diseases in the respiratory system, including lung cancer. However, the precise mechanisms through which PM2.5 induces respiratory diseases are still unclear. In this study, we demonstrated that CD4+ and CD8+ T cells following PM2.5 treatment demonstrated significantly elevated mRNA and protein levels of interferon (IFN)-γ, interleukin (IL)-10, IL-17, and IL-21 production. This increase in cytokines required the presence of macrophages, such that CD4+ and CD8+ T cells treated with PM2.5 in the absence of macrophages did not present higher IFN-γ, IL-10, or IL-21 expression. In contrast, PM2.5-treated macrophages could significantly upregulate T cell cytokine secretion, even when excess PM2.5 was removed from cell culture. We also observed a macrophage-dependent upregulation of granzyme A and granzyme B expression by CD4+ and CD8+ T cells following PM2.5 treatment. These PM2.5-stimulated CD4+ and CD8+ T cells potently induced the death of human bronchial epithelial (HBE) cells. Interestingly, the CD4+ and CD8+ T cells presented synergistic effects at inducing HBE cytotoxicity, such that CD4+ T cells and CD8+ T cells combined resulted in higher HBE cell death than the sum of the separate effects of CD4+ T cells and CD8+ T cells. While blocking cytotoxic molecule release significantly compromised the T cell-mediated cytotoxicity against HBE cells, blocking IFN-γ, but not IL-10, could also slightly but significantly reduce T cell-mediated cytotoxicity. Together, these data demonstrated that PM2.5 could promote the inflammation of cytotoxicity of T cells in a macrophage-dependent manner. In addition, PM2.5-treated macrophages presented long-lasting proinflammatory effects on T cells.

Function of follicular helper T cell is impaired and correlates with survival time in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) represents one of the most common and aggressive cancers worldwide. The PD-1/PD-L1 interaction plays important roles in cancer immunology, and expression of PD-L1 has been discovered in NSCLC tumor cells. Since follicular helper T (Tfh) cells have characteristic high PD-1 expression, we therefore investigated the inflammatory status of Tfh in NSCLC. CD4+CXCR5+ T cell population was examined to define Tfh cells. Data showed that frequency of Tfh cells in peripheral blood was significantly lower in NSCLC patients than in healthy controls. In both primary and metastatic tumors, infiltration of Tfh cells was observed, suggesting that they participated in the antitumor immunity of NSCLC patients. Compared to other T cell subsets, the Tfh cells from the peripheral blood and the resected tumors of NSCLC patients presented elevated apoptosis and reduced proliferation capacity. The Tfh cells from NSCLC patients were also less effective at downregulating IgD and upregulating CD27 expression in naive B cells, and induced less IgM, IgG and IgA secretion, than those from healthy controls. We then found that the survival time from the date of surgery was positively correlated with the frequency of tumor-infiltrating Tfh cells in NSCLC subjects. Overall, the results from this study demonstrated that the Tfh cells were likely involved in the antitumor immunity and were associated with better clinical outcomes, but suffered strong immunosuppression in NSCLC. Enhancing the Tfh cell activity therefore represents a potential therapeutic strategy in NSCLC.

Interleukin 17A genetic variations and susceptibility to non-small cell lung cancer.

Lung cancer is the leading cause of cancer-related death, in which non-small cell lung cancer (NSCLC) is the most common type. Evidence have shown that interleukin 17 (IL-17) greatly involves in human immune responses. In this study, we investigated the effect of IL-17 on NSCLC by examining the association between IL-17A genetic polymorphisms and the susceptibility to NSCLC. IL-17A -420A/G and IL-17A -73G/A polymorphisms were detected in 330 NSCLC patients and 382 healthy controls. We found that subjects carrying -73GA genotype or AA genotype had 2.09-fold or 2.52-fold increased risk of NSCLC than those with -73GG genotype [odds ratio (OR) = 2.09, 95% confidence interval (CI), 1.46 - 2.98, p < 0.001; OR = 2.52, 95% CI, 1.30-4.88, p = 0.005, respectively). However, the IL-17A -420A/G did not reveal any correlation with the cancer. Further investigation showed that prevalence of IL-17A -73GA genotype and A allele were significantly increased in adenocarcinoma patients (OR = 1.75, 95% CI, 1.08-2.86, p = 0.024, OR = 1.57, 95% CI, 1.09-2.28, p = 0.016, respectively). We also evaluated the effect of the polymorphisms on gene expression, and identified that peripheral blood mononuclear cells with IL-17A -73GA and AA genotypes produced significantly higher level of IL-17 than the cells with IL-17A -73GG genotype. Our results suggest that IL-17A -73G/A genetic variations may upregulate IL-17 expression and are associated with increased susceptibility to NSCLC.

The significance of MAGED4 expression in non-small cell lung cancer as analyzed by real-time fluorescence quantitative PCR.

The aim of this study was to detect differences in the expression levels of melanoma-associated antigen D4 (MAGED4) mRNA between non-small cell lung cancer (NSCLC) tissues and normal tissues, and to compare differences in the expression levels of MAGED4 in tumor patients. Patients were grouped according to age, gender, smoking history, tumor size, pathological classification, degree of lung cancer cell differentiation and presence of lymph node metastasis. The expression levels of MAGED4 were detected using real-time fluorescence quantitative PCR. MAGED4 expression was higher in squamous cell carcinomas compared to adenocarcinomas (P<0.05), in poorly differentiated tissues compared to well-differentiated tissues (P<0.05), and in patients with lymph node metastasis compared to patients without lymph node metastasis (P<0.05). MAGED4 may be used as a specific antigen for NSCLC to influence the improvement of diagnosis, prognosis and immunological therapy outcomes in lung cancer patients.

Tumour length is an independent prognostic factor of esophageal squamous cell carcinomas.

BACKGROUND: The latest version of the American Joint Committee on Cancer (AJCC) TNM staging system has not comprehensively evaluated the impact of tumour length on survival in patients with esophageal squamous cell carcinoma. Our study explored the relationship between tumour length and clinicopathological characteristics as well as long-term survival. METHODS: All 202 cases of esophageal resections done from January 1, 2004 to December 31, 2008 in Huashan Hospital, Fudan University were reviewed and followed up. RESULTS: Patients with tumour length = 3 cm were related to more advanced tumour stage (χ(2) = 55.9, P < 0.001), more metastatic lymph nodes (χ(2) = 14.6, P < 0.001), increased metastatic lymph node ratio χ(2) = 16.1, P < 0.001) and worse overall TNM stage (χ(2) = 48.1, P < 0.001). Univariate and multivariate analyses indicated that tumour length was a significant prognostic risk factor (95% CI 0.235 - 0.947, P = 0.035). Subgroup analyses disclosed that tumour length was a valuable prognostic predictor in patients with lower T stage, absence of metastatic lymph nodes and lower TNM stage. CONCLUSIONS: Esophageal tumour length is a predictive factor for long-term survival especially for lower tumour stage, absence of metastatic lymph nodes and lower TNM stage patients. Tumour length should be incorporated in the staging system as an important grouping factor for better prognostic evaluation.

The mechanism of mimecan transcription induced by glucocorticoid in pituitary corticotroph cells.

Mimecan, a secretary protein that is expressed in mouse and human pituitary corticotroph cells, is up-regulated by glucocorticoids (GC) in the corticotroph cells via classical glucocorticoid receptor (GR) pathways. In this study, we further explore the GC mechanism for mimecan expression in these cells. Five putative GR response elements (GREs) were identified in ~2 kb of the mimecan promoter by programme analysis. An EMSA assay further indicated that these putative GREs were bound by the GR. Moreover, three proximal GREs are conserved between species. Although luciferase assays showed that the -1474/+43 region of the mimecan promoter achieved the highest expression of mimecan, the -803/+43 mimecan promoter region was sufficient for the GC-mediated expression of mimecan. The mutations of three conserved GREs located in the -1474/+43 mimecan promoter region did not affect mimecan transcription, which suggests that the effects of GC on mimecan are independent of the GREs in the promoter. In addition, cycloheximide, a protein synthesis inhibitor, blocked GC-induced mimecan expression in AtT-20 cells. Taken together, these results suggest that, although there are 3-5 GREs in the mimecan promoter, GC may regulate mimecan transcription indirectly through the synthesis of intermediate proteins and not through the GREs in pituitary corticotroph cells.

Application of the titanium plate fixation system in sternum transverse incisions.

The purpose of this study was to review the application of the titanium plate fixation system in sternum transverse incisions and assess its advantages over the conventional methods of steel wire fixation. Sternal healing of 249 patients who underwent a thymectomy and/or excision of the thymoma with a transverse sternal incision was compared between patients who underwent titanium plate fixation or steel wire fixation. Short-term results: The stability of the sternum was significantly superior in the titanium plate group compared with the steel wire group (P < 0.01). Out-of-bed activities started earlier for patients in the titanium plate group compared with the steel wire group (P < 0.01). Long-term results: The sternal healing rate in the titanium plate group was significantly higher than the steel wire group (P < 0.05). Titanium plate fixation improves the postoperative sternal stability in patients with transverse sternal incisions for thymectomy and/or excision of a thymoma. Titanium plate fixation also reduces postoperative pain, enhances the patient's physical activity, and decreases the long-term nonunion rate of the sternum.

Mimecan in pituitary corticotroph cells may regulate ACTH secretion and the HPAA.

Mimecan is a protein of unknown function that is expressed in the pituitary tissues of mouse and human. In this study, we observed the function of mimecan on the proopiomelanocortin (POMC) gene in the pituitary and the hypothalamo-pituitary-adrenal axis (HPAA). Incubating pituitary corticotroph AtT-20 cells with recombinant mimecan protein stimulated adrenocorticotrophic hormone (ACTH) secretion without significantly up-regulating POMC gene expression. In addition, pituitary corticotroph AtT-20 cell corticotropin-releasing hormone receptor 1 (CRHR1) gene expression was induced by mimecan. Interestingly, long-term mimecan overexpression in corticotroph cells increased CRHR1 mRNA levels while slightly decreasing POMC mRNA expression and ACTH secretion. Using mimecan knockout mice, we found that, although the serum ACTH concentration was not significantly different between wild type and mimecan knockout mice under basal conditions, the serum ACTH level was relatively lower in mimecan knockout mice after treatment with corticotropin-releasing hormone (CRH). Meanwhile, we observed that POMC and CRHR1 gene expression decreased in primary cultured knockout mouse pituitary cells compared with wild type cells. Taken together, these data suggest that mimecan expressed in pituitary corticotroph cells mainly regulates ACTH secretion in the pituitary and coordinates the HPAA.

Glucocorticoid up-regulates mimecan expression in corticotroph cells.

Mimecan is a protein of unknown function that is expressed in the pituitary. The aim of this study is to clarify the regulation and intracellular localisation of mimecan gene expression in the pituitary. With immunohistochemistry, we observed that mimecan protein was co-expressed with ACTH in pituitary corticotroph cells. Northern and Western blot analyses revealed that mimecan expression and secretion in corticotroph cells were up-regulated by treating AtT-20 cells with glucocorticoid. Meanwhile, mimecan expression in rat primary culture pituitary cells was also promoted by glucocorticoid. Co-incubation of AtT-20 cells with RU486 and glucocorticoid completely reversed the induction of mimecan gene expression by glucocorticoid. In addition, luciferase reporter assays showed that the -1474/+43 promoter region of mimecan was sufficient for glucocorticoid-responsive mimecan expression. These data collectively suggest that mimecan expressed in pituitary corticotroph cells is increased by glucocorticoid and that the up-regulation may be mediated by the classical GR pathways.

Expression of adiponectin receptors in mouse adrenal glands and the adrenocortical Y-1 cell line: adiponectin regulates steroidogenesis.

Obesity is frequently associated with malfunctions of the hypothalamus-pituitary-adrenal (HPA) axis and hyperaldosteronism, but the mechanism underlying this association remains unclear. Since the adrenal glands are embedded in adipose tissue, direct cross-talk between adipose tissue and the adrenal gland has been proposed. A previous study found that adiponectin receptor mRNA was expressed in human adrenal glands and aldosterone-producing adenoma (APA). However, the expression of adiponectin receptors in adrenal glands has not been confirmed at the protein level or in other species. Furthermore, it is unclear whether adiponectin receptors expressed in adrenal cells are functional. We found, for the first time, that adiponectin receptor (AdipoR1 and AdipoR2) mRNA and protein were expressed in mouse adrenal and adrenocortical Y-1 cells. However, adiponectin itself was not expressed in mouse adrenal or Y-1 cells. Furthermore, adiponectin acutely reduced basal levels of corticosterone and aldosterone secretion. ACTH-induced steroid secretion was also inhibited by adiponectin, and this was accompanied by a parallel change in the expression of the key genes involved in steroidogenesis. These findings indicate that adiponectin may take part in the modulation of steroidogenesis. Thus, adiponectin is likely to have physiological and/or pathophysiological significance as an endocrine regulator of adrenocortical function.

Different expression of mimecan as a marker for differential diagnosis between NSCLC and SCLC.

Mimecan mRNA was present in a limited number of mouse and human tissues, however, abundant mimecan mRNA was observed in the lung tissue. Therefore, we hypothesize that mimecan could serve as a biomarker for differentiating various histological types of lung cancers. In humans, the mimecan mRNA was found most abundant in ovary and less abundant in lung by using Northern blot analysis. Moreover, the mimecan was expressed strongly in the epithelial cells of the bronchial wall and weaker in the epithelial cells of the alveolar sacs by in situ hybridization and immunohistochemical analysis. Furthermore, the mimecan immunoreactivity was found in 103 (97.2%) of 106 non-small cell lung cancers (NSCLCs). Nevertheless, a large majority of small cell lung cancers (SCLCs) (50/56, 89.3%) showed negative immunoreactivity to mimecan polyclonal antibody. A significant difference of mimecan immunoreactivity was found between NSCLC and SCLC (P<0.00001). This is the first study showing that mimecan could serve as an excellent pathological biomarker to distinguish NSCLCs from SCLCs.

The mimecan gene expressed in human pituitary and regulated by pituitary transcription factor-1 as a marker for diagnosing pituitary tumors.

CONTEXT: Mimecan, a secretory protein, belongs to a family of small leucine-rich proteoglycans (SLRPs). The physiological functions of mimecan have not been fully understood. OBJECTIVE: We hypothesize that the mimecan gene expressed in the human pituitary and regulated by pituitary transcription factor-1 (Pit-1) might act as a marker for diagnosing pituitary tumors. DESIGN: The clinical aspect of our work was a cross-sectional study. SETTING AND PATIENTS: In total, 20 pituitary tumor samples were collected from January 1, 2002, to December 30, 2002, in Ruijin Hospital, Shanghai, China. INTERVENTION: The number of pituitary tumors was limited. Collection of more pituitary tumor samples for additional observation will be necessary. MAIN OUTCOME MEASURES: The main outcomes were measured by Northern blot, in situ hybridization, immunohistochemical analysis, and so on. RESULTS: The mimecan gene was expressed at a moderate level in the mouse pituitary gland by Northern blot analysis. Expression of mimecan mRNA and protein is also observed in the human anterior pituitary gland. Luciferase reporter analysis and electrophoretic mobility shift assays show that Pit-1 activates the human mimecan promoter through Pit-1 response element sites. In addition, our data also show that almost all the ACTH- or GH-positive pituitary tumors likely express mimecan protein, and only a portion of prolactin-, TSH-, FSH-, and LH-positive pituitary tumors express mimecan protein. CONCLUSIONS: This work provides insight into the regulating mechanism of mimecan in pituitary and suggests that mimecan may be an unidentified pituitary secretory protein, and certain pituitary cells secreting ACTH or GH also secrete mimecan.