Zyxin (ZYX) promotes invasion and acts as a biomarker for aggressive phenotypes of human glioblastoma multiforme.

Glioblastoma multiforme (GBM) is characterized by highly invasive growth, which leads to extensive infiltration and makes complete tumor excision difficult. Since cytoskeleton proteins are related to leading processes and cell motility, and through analysis of public GBM databases, we determined that an actin-interacting protein, zyxin (ZYX), may involved in GBM invasion. Our own glioma cohort as well as the cancer genome atlas (TCGA), Rembrandt, and Gravendeel databases consistently showed that increased ZYX expression was related to tumor progression and poor prognosis of glioma patients. In vitro and in vivo experiments further confirmed the oncogenic roles of ZYX and demonstrated the role of ZYX in GBM invasive growth. Moreover, RNA-seq and mass-spectrum data from GBM cells with or without ZYX revealed that stathmin 1 (STMN1) was a potential target of ZYX. Subsequently, we found that both mRNA and protein levels of STMN1 were positively regulated by ZYX. Functionally, STMN1 not only promoted invasion of GBM cells but also rescued the invasion repression caused by ZYX loss. Taken together, our results indicate that high ZYX expression was associated with worse prognosis and highlighted that the ZYX-STMN1 axis might be a potential therapeutic target for GBM.

Golgi Fragmentation in Human Patients with Chronic Atrial Fibrillation: A New Aspect of Remodeling.

BACKGROUND: Atrial fibrillation (AF) is the most common chronic arrhythmia in elderly people and is accompanied by remodeling processes. While much is known about changes in ionic channels and in extracellular matrix, less is known about possible changes of intracellular structures. OBJECTIVE: We wanted to investigate, whether AF may also affect the structure of the Golgi apparatus and the microtubular network. METHODS: One-hundred fifty-three cardiac surgery patients were investigated [n = 24 in sinus rhythm (SR) and n = 129 with chronic AF of >1 year duration]. Tissue samples of the left atrial free wall were examined immunohistochemically. Golgi apparatus was detected by GM130 and its phosphorylated isoform. Furthermore, we investigated the length of the microtubules by α-tubulin staining. We also measured stathmin (phospho-S37), which is known to induce microtubule depolymerization. In addition, we investigated the cyclin-dependent kinase cdk5-activation, a typical stimulus for Golgi fragmentation, by measuring membrane-associated cdk5. RESULTS: We found significant fragmentation of the Golgi apparatus in AF together with a reduced fragment size. Significant more fragments of the Golgi were found lateral to the nucleus in AF, while the Golgi in SR was located more to the polar side of the nucleus, that is, in the longitudinal axis of the cell. This was accompanied by a significant reduction of the number of tubulin strands longer than 10 µm. These changes did not go along with an activation of stathmin, but with an increase in membrane association of cdk5. CONCLUSIONS: The present data may show that AF associated remodeling also involves intracellular remodeling of the Golgi-microtubular apparatus.

Activation of an AKT/FOXM1/STMN1 pathway drives resistance to tyrosine kinase inhibitors in lung cancer.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) have demonstrated clinical benefits in the treatment of several tumour types. However, the emergence of TKI resistance restricts the therapeutic effect. This study uses non-small cell lung cancer (NSCLC) to explore the mechanisms contributing to TKI resistance in tumours. METHODS: Biological phenotypes and RNA microarray expression data were analysed in NSCLC cells with and without TKI pretreatment. Specific inhibitors and siRNAs were used to validate the direct involvement of an AKT/FOXM1/STMN1 pathway in TKI resistance. Patients' tissues were analysed to explore the clinical importance of FOXM1 and STMN1. RESULTS: In vitro and in vivo studies showed that TKIs induced the enrichment of cancer stem cells (CSC), promoted epithelial to mesenchymal transition (EMT), and conferred multidrug resistance on NSCLC cells in a cell type- and TKI class-dependent manner. Mechanistically, TKIs activated an AKT/FOXM1/STMN1 pathway. The crucial role of this pathway in TKI-induced enrichment of CSC and drug resistance was verified by silencing FOXM1 and STMN1 or blocking the AKT pathway. Additionally, overexpression of STMN1 was associated with upregulation of FOXM1 in advanced NSCLC patients, and STMN1/FOXM1 upregulation predicted a poor outcome. CONCLUSIONS: Our findings elucidate an additional common mechanism for TKI resistance and provide a promising therapeutic target for reversing TKI resistance in NSCLC.

High expression of karyopherin-α2 and stathmin 1 is associated with proliferation potency and transformation in the bile duct and gall bladder epithelia in the cases of pancreaticobiliary maljunction.

BACKGROUNDS AND OBJECTIVES: Pancreaticobiliary maljunction (PBM) may be associated with an increased frequency of gall bladder cancer with no bile duct dilation. Karyopherin-α2 (KPNA2) and stathmin 1 (STMN1) were reported to play important roles in carcinogenesis and cancer progression. METHODS: Fifteen patients with PBM who underwent surgical resection between 1999 and 2014 were included in this study. Using immunohistochemistry, we investigated the expression of p53, Ki-67, KPNA2, and STMN1 in normal biliary tract epithelium, hyperplastic epithelium, and cholangiocarcinoma (CC) tissues. RESULTS: Nuclear expression of KPNA2, p53, and Ki-67 expression was detected in hyperplastic epithelium and CC tissues. High KPNA2 expression was significantly associated with gender (P = 0.04), p53 nuclear accumulation (P = 0.00435), and Ki-67 expression (P = 0.0443) in the gall bladder and bile duct of PBM. On the other hand, STMN1 was only expressed in CC tissues and was not observed in normal bile duct and hyperplastic epithelia. CONCLUSIONS: KPNA2 might be a useful marker of hyperplasia, dysplasia, and carcinogenicity in patients with PBM. STMN1 evaluation might be a cancer-specific marker for CC patients with PBM similar as that for other cancers. J. Surg. Oncol. 2016;114:462-468. © 2016 Wiley Periodicals, Inc.

Identification of stathmin 1 during peri-implantation period in mouse endometrium by a proteomics-based analysis.

In this work we aimed to identify the differentially expressed proteins and their potential roles during peri-implantation period through proteomics-based approach. Adult healthy female mice were mated naturally with fertile males to produce pregnancy. The models of pseudopregnancy, delayed implantation, and artificial decidualization were established. The protein profile between pre-implantation (D1) and implantation (D5) period was compared by two-dimensional electrophoresis (2-DE) and identified by mass spectrometry (MS). 2-DE yielded comparative images presenting over 500 protein spots in D1 and D5 mouse endometrium. 15 proteins were identified, of which stathmin 1, Apo-A1, hnRNP H3, transgelin 2 and arginase 1 were validated by western blotting. Stathmin 1 expression did not change in pseudopregnancy, but activation of implantation, or induction of decidualization increased it dramatically. Under non-pregnant status, progesterone alone or in combination with17ß-estradiol increased it dramatically. Our results clarified the protein profile in mouse endometrium during implantation. The specific expression profile of stathmin 1 suggested that it should be involved in implantation and serve as a potential regulator of this process. These findings may contribute to the better understanding of the molecules events during embryo implantation, and subsequently improve the ability to treat infertility.

Overexpression of stathmin 1 confers an independent prognostic indicator in nasopharyngeal carcinoma.

Data mining on public domain identified that stathmin 1 (STMN1) transcript was significantly higher expressed in nasopharyngeal carcinoma (NPC). Also known as the oncoprotein 18, STMN1 performs an important function in regulating rapid microtubule remodeling of the cytoskeleton in response to the cellular conditions. Immunoexpression of STMN1 was retrospectively assessed in biopsies of 124 consecutive NPC patients without initial distant metastasis and treated with consistent guidelines. The outcome was correlated with clinicopathological features and patient survivals. Results indicated that high STMN1 expressions (50 %) were correlated with advanced age (p = 0.027), higher T stage (p = 0.003), and overall clinical stage (p = 0.006) by the 7th American Joint Committee of Cancer Staging. In multivariate analyses, high STMN1 expression emerged as an independent prognosticator for worse disease-specific survival (p = 0.001), distal metastasis-free survival (p = 0.003), and local recurrence-free survival (p = 0.006). Exogenous expression of E2F transcription factor 1 (E2F1) or/and its dimeric partner, transcription factor Dp-1 (TFDP1), notably induced the STMN1 protein level in a NPC-derived cell line, TW01. Accordingly, high STMN1 protein level is commonly associated with adverse prognosticators and confers tumor aggressiveness in patients with NPC, and its upregulation might be attributed to E2F1 and/or TFDP1 transactivation.

Proteomic analysis of colorectal cancer metastasis: stathmin-1 revealed as a player in cancer cell migration and prognostic marker.

Metastasis accounts largely for the high mortality rate of colorectal cancer (CRC) patients. In this study, we performed comparative proteome analysis of primary CRC cell lines HCT-116 and its metastatic derivative E1 using 2-D DIGE. We identified 74 differentially expressed proteins, many of which function in transcription, translation, angiogenesis signal transduction, or cytoskeletal remodeling pathways, which are indispensable cellular processes involved in the metastatic cascade. Among these proteins, stathmin-1 (STMN1) was found to be highly up-regulated in E1 as compared to HCT-116 and was thus selected for further functional studies. Our results showed that perturbations in STMN1 levels resulted in significant changes in cell migration, invasion, adhesion, and colony formation. We further showed that the differential expression of STMN1 correlated with the cells' metastatic potential in other paradigms of CRC models. Using immunohistochemistry, we also showed that STMN1 was highly expressed in colorectal primary tumors and metastatic tissues as compared to the adjacent normal colorectal tissues. Furthermore, we also showed via tissue microarray analyses of 324 CRC tissues and Kaplan-Meier survival plot that CRC patients with higher expression of STMN1 have poorer prognosis.

Stathmin expression and its relationship to microtubule-associated protein tau and outcome in breast cancer.

BACKGROUND: Microtubule-associated proteins (MAPs) endogenously regulate microtubule stability. Here, the prognostic value of stathmin, a destabilizing protein, was assessed in combination with MAP-tau, a stabilizing protein, in order to evaluate microtubule stabilization as a potential biomarker. METHODS: Stathmin and MAP-tau expression levels were measured in a breast cancer cohort (n = 651) using the tissue microarray format and quantitative immunofluorescence (AQUA) technology, then correlated with clinical and pathological characteristics and disease-free survival. RESULTS: Univariate Cox proportional hazard models indicated that high stathmin expression predicts worse overall survival (hazard ratio [HR] = 1.48; 95% confidence interval [CI] = 1.119-1.966; P = .0061). Survival analysis showed 10-year survival of 53.1% for patients with high stathmin expression versus 67% for low expressers (log-rank, P < .003). Cox multivariate analysis showed high stathmin expression was independent of age, menopausal status, nodal status, nuclear grade, tumor size, and estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression (HR = 1.19; 95% CI = 1.03-1.37; P = .01). The ratio of MAP-tau to stathmin expression showed a positive correlation to disease-free survival (HR = 0.679; 95% CI = 0.517-0.891; P = .0053) with a 10-year survival of 65.4% for patients who had a high ratio of MAP-tau to stathmin versus 52.5% 10-year survival rate for those with a low ratio (log-rank, P = .0009). Cox multivariate analysis showed the ratio of MAP-tau to stathmin was an independent predictor of overall survival (HR = 0.609; 95% CI = 0.422-0.879; P = .008). CONCLUSIONS: Low stathmin and high MAP-tau are associated with increased microtubule stability and better prognosis in breast cancer.

Analysis of different medulloblastoma histotypes by two-dimensional gel and MALDI-TOF.

OBJECTIVE: The purpose of this study is to detect different protein profiles in medulloblastoma (MDB) that may be clinically relevant and to check the correspondence of histological classification of MDB with proteomic profiles. MATERIALS AND METHODS: Surgical specimens, snap frozen at the time of neurosurgery, entered the proteomic study. Eight samples from patients (age range, 4 months-26 years) with different MDB histotypes (five classic, one desmoplastic/nodular, one with extensive nodularity, and one anaplastic) were analyzed by two-dimensional gel electrophoresis. One sample for each histotype was further characterized by matrix-assisted laser desorption/ionization time of flight mass spectrometry analysis. RESULTS: Eighty-six unique proteins were identified and compared to histology, with the determination of proteins expressed by single histotypes and of a smaller number of proteins shared by two or three histotypes. The sharp difference of protein expression was found to be in agreement with WHO histological classification, with the identification of type-specific proteins with limited overlapping between histotypes. CONCLUSION: Proteomic analysis confirmed and strengthened the difference between histotypes as biologically relevant. Cluster analysis enhanced the distance of extensive nodularity MDB from other histotypes. Possible innovative approaches to therapy may rely upon a proteomic-based classification of MDB tightly correlated to histology. The utility of snap freezing tumoral samples must be stressed and should become a mandatory task for pathologists.

p16 is superior to Stathmin-1 and HSP27 in identifying cervical dysplasia.

BACKGROUND: The aim of this study was to determine how Stathmin-1 and Heat Shock Protein 27 (HSP27) can be used as adjunctive biomarkers to differentiate high-grade dysplasia from benign/reactive lesions in cervical tissues. In addition, we aimed to see if any of these markers can differentiate endometrial from endocervical adenocarcinomas. METHODS: Fifty cases including benign cervical tissue, low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), adenocarcinoma in situ of the endocervix, invasive endocervical adenocarcinoma, and endometrial adenocarcinoma were selected. Stathmin-1 and HSP27 immunohistochemistry (IHC) were performed for each case and the results were compared to the previously available p16 IHC stains. RESULTS: p16 stained positively in 100% of HSIL, endocervical adenocarcinoma in situ, and invasive endocervical cases. Stathmin-1 stained positively in 43% of HSIL and 90% of endocervical adenocarcinoma in situ and all invasive endocervical cases. Stathmin-1 and p16 were negative in all benign cervical samples. Stathmin-1, HSP27, and p16 stained 100% of LSIL cases. HSP27 stained indiscriminately, including 100% of benign cervical tissue. 87% of the endometrial adenocarcinomas stained positively for p16, Stathmin-1, and HSP27. CONCLUSION: p16 remains superior to both Stathmin-1 and HSP27 in differentiating dysplasia from benign, reactive changes of the cervix.

Intact mass detection, interpretation, and visualization to automate Top-Down proteomics on a large scale.

Applying high-throughput Top-Down MS to an entire proteome requires a yet-to-be-established model for data processing. Since Top-Down is becoming possible on a large scale, we report our latest software pipeline dedicated to capturing the full value of intact protein data in automated fashion. For intact mass detection, we combine algorithms for processing MS1 data from both isotopically resolved (FT) and charge-state resolved (ion trap) LC-MS data, which are then linked to their fragment ions for database searching using ProSight. Automated determination of human keratin and tubulin isoforms is one result. Optimized for the intricacies of whole proteins, new software modules visualize proteome-scale data based on the LC retention time and intensity of intact masses and enable selective detection of PTMs to automatically screen for acetylation, phosphorylation, and methylation. Software functionality was demonstrated using comparative LC-MS data from yeast strains in addition to human cells undergoing chemical stress. We further these advances as a key aspect of realizing Top-Down MS on a proteomic scale.

Overexpression of class III beta-tubulin predicts good response to taxane-based chemotherapy in ovarian clear cell adenocarcinoma.

PURPOSE: Of the various microtubule-associated molecules, beta-tubulin III has been reported to be closely associated with the therapeutic efficacy of taxane-based chemotherapy against ovarian cancer. Stathmin and microtubule-associated protein 4 (MAP4) have been reported to play an important role in microtubule stabilization. In this study, we investigated whether expression of these microtubule-associated factors affects the therapeutic efficacy of taxane-based chemotherapy in ovarian clear cell adenocarcinoma. EXPERIMENTAL DESIGN: Drug sensitivity of paclitaxel or cisplatin was assessed in ovarian cancer cell lines treated with small interfering RNA of tubulin isoforms, MAP4, and stathmin. We examined 94 surgically resected ovarian clear cell adenocarcinoma specimens from patients treated with taxane-containing regimens (n=44) and with taxane-free regimens (n=50), using immunohistochemistry to detect expression of beta-tubulin III, stathmin, and MAP4. RESULTS: Knockdown of beta-tubulin III and IV specifically conferred drug resistance to paclitaxel in one ovarian cancer cell line, but not to other molecules. Estimated overall survival revealed a significant synergistic effect between taxane and beta-tubulin III in patients with ovarian clear cell adenocarcinoma. Of three microtubule-related molecules, among the taxane-based chemotherapy group, cases with higher beta-tubulin III expression were associated with a significantly more favorable prognosis compared with those having lower beta-tubulin III expression. By contrast, there was no statistical significance in the synergistic relationships between stathmin and taxane or between MAP4 and taxane. CONCLUSIONS: Taxane-based chemotherapy was effective for patients with ovarian clear cell adenocarcinomas who were positive for beta-tubulin III but not for those who were negative for these proteins.

Affective profiling for anxiety-like behavior in a rodent model of mTBI.

Mild traumatic brain injury is a common outcome of blast exposure, and current literature indicates high rates of comorbid posttraumatic stress disorder (PTSD) in military personnel. Blast-exposed rats display PTSD-like behavior, suggesting relationships may exist between PTSD and blast exposure. Other studies demonstrate the roles of stathmin and corticosterone associated with fear- and anxiety-like behaviors in rodent models. Furthermore, studies have observed ranges of responses to both physical and psychological trauma in animal populations (Elder 2012, Ritov 2016). This study exposed rodents to repeated blast overpressure (BOP) and analyzed behavioral responses and molecular variables at 3 weeks and 6 months after exposure. We applied a modified version of a previously reported behavioral profiling approach that separates "affected" and "unaffected" rats based on the presence of anxiety-like behaviors (Ritov, 2016). We report that "affected" 3 week animals showed higher plasma corticosterone and amygdalar stathmin levels, while "affected" 6 month animals had lower prefrontal cortex stathmin. Higher corticosterone also paralleled anxiety behavior in "affected" 3 week animals, which was not observed in 6 month animals, indicating possible negative feedback loop mechanisms. Elevated levels of amygdalar stathmin correlated with anxiety behaviors in "affected" 3 week and 6 month animals, indicating sustained molecular changes. We conclude that this unique analysis may provide more information about response to blast. This type of analysis should also be considered when treating clinical populations, since individual differences may affect behavioral and long-term outcomes. Future studies should elucidate relationships of stress and fear responses in the context of BOP.

Comparative proteomic analysis of differentially expressed proteins between K562 and K562/ADM cells.

BACKGROUND: Multidrug resistance to chemotherapeutic agents is an important clinical problem during the treatment of leukemia. The resistance process is multifactorial. To realize the total factors involved in multidrug resistance, we analyzed the differentially expressed proteins of K562 and K562/ADM cells and we investigated one of the up-regulated proteins (CRKL) using siRNA to determine its role in K562/ADM cells. METHODS: Altered protein expressions between K562/S (K562 ADM-sensitive cell line) and K562/ADM (K562 multidrug resistant cell line induced by adriamycin) were identified by 2D-DIGE coupled with mass spectrometry. Meanwhile, we confirmed the differential expression of CRKL and Stathmin in both K562 and K562/ADM cells by Western blot analysis. Furthermore, we used RNA interference to silence the CRKL gene expression. RESULTS: Among the 9 differentially expressed proteins, 3 were up-regulated in K562/ADM cells, while 6 were down-regulated in the K562/ADM cells compared with its parent cell line. The expression of CRKL was up-regulated significantly in K562/ADM cells, and it can be decreased by recombinant lentivirus. Moreover, the multidrug resistance of K562/ADM cells was efficiently reversed by silence of CRKL gene expression. CONCLUSIONS: The data provided the differentially expressed proteins in K562 and its resistant cell line and highlights the power of 2D-DIGE for the discovery of resistance markers in cancer. We found CRKL may be a new protein involved in the multidrug resistance of leukaemia cells.

A feasibility and safety study of concurrent chemotherapy based on genetic testing in patients with high-risk salivary gland tumors: Preliminary results.

BACKGROUND: This prospective study was conducted to evaluate the feasibility and safety of customized chemotherapy regimens based on the gene characteristics of salivary gland tumors. METHODS: Patients were enrolled with histologically confirmed intermediate or high grade, stage T3-4, N1-3 disease, and T1-2, N0 patients with a close (≤1 mm) or microscopically positive surgical margin were also enrolled in the study. All patients received radical surgery and postoperative concurrent chemoradiotherapy. To evaluate the responsiveness of therapies, the chemotherapy regimen was based on gene targets, ß-tubulin III, ABCB1, STMN1, and CYP1B1 (for docetaxel) and TYMS (for pemetrexed). The primary endpoints were treatment compliance and acute toxicities. RESULTS: A total of 20 patients were enrolled between September 2013 and January 2016. The median age was 46 years (range: 23-70 years). Genetic testing showed that 8 patients may have been sensitive to docetaxel, 5 patients may have been sensitive to pemetrexed, and 7 patients sensitive to either docetaxel or pemetrexed. All patients received the full dose of radiation. A total of 19 patients (95%) completed 2 cycles of concurrent chemotherapy (CCT). One patient treated concurrently with pemetrexed experienced grade 3 neutropenia. Three patients experienced grade 3 oral mucositis, and 2 patients experienced grade 3 dermatitis. CONCLUSION: Our study demonstrated that a CCT selecting method based on the gene targets associated with drug sensitivity was clinically feasible and safe. Further studies enrolled more patients with longer follow-up times are needed to confirm the clinical efficacy of this CCT selecting method.

[Differential analysis of proteomic profiles between cryptorchid and normal mouse testes].

To screen factors related to spermatogonial stem cell (SSC) proliferation, and to investigate the mechanism of infertility caused by cryptorchidism, ten-day-old Kunming (KM) mice were used and experimental cryptorchidism was conducted. On the 35th day after cryptorchid operation, the left testes were fixed in Bouin's fluid and used for histological analysis. The testes of 45-day-old mice were subjected to the same histological analysis, and it was found that they contained germ cells at every stage of development, from SSCs to sperm, indicating that the animals were fully sexually mature at this age. While in experimental cryptorchid mice, the spermatogenesis was arrested at the stage of spermatocytes, and only spermatogonia and primary spermatocytes were present in cryptorchid testes. The proportion of spermatogonia to other types of germ cells was much higher than that in sexually mature mice. On the other hand, the right testes were used for proteomic analysis. The total protein in testes was extracted on the 35th day after cryptorchid operation. The differentially expressed proteins in cryptorchid mice and sexually mature mice were screened and compared by the proteomic techniques. Through the separation of two-dimensional gel electrophoresis (2-DE), 20 differential protein spots were found, and 9 of them were digested and identified by the matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrum. In cryptorchid mice, 6 out of 9 proteins were down-regulated, and 3 were up-regulated. Among these proteins, 4 proteins were identified, and they were Stathmin, phosphatidylethanolamine-binding protein1 (PEBP1), HES-related basic helix-loop-helix protein (HERP), and one unnamed protein (we temporarily named it Px). More Stathmin, PEBP1 and Px were expressed in sexually mature mice than in experimental cryptorchid mice. But HERP1 was the other way round. In the present study, we have screened 4 proteins related to cryptorchidism. It is helpful to study the mechanism of SSC proliferation and infertility caused by cryptorchidism.

Overexpression of STMN1 is associated with the prognosis of meningioma patients.

There is a small part of the pathological type of the meningioma has a malignant tendency and patients have the poor prognosis. Looking for effective biomarkers to predict the degree of malignancy of the tumors, will help us to better manage the patient and guide the treatment. The present study aims at investigating the prognostic value of the expression of Stathmin in a series of meningiomas of different grade. We integrated eight published microarray datasets of meningiomas to screen grade biomarkers in meningiomas patients using the WebArrayDB platform. We focused on Stathmin, Using formalin-fixed paraffin-embedded (FFPE) tumor samples, we corroborated the relationship between Stathmin and patient outcomes using qRT-PCR for gene expression. We also found expression of Stathmin that atypical/anaplastic meningiomas have higher expression than benign meningiomas (p<0.01). No correlation between Stathmin expression and age, gender and tumor extent of resection was found (p>0.05). Moreover, increased Stathmin expression was correlated to higher meningioma grade and shorter disease-free survival (DFS) of meningioma patients with Simpson I resection. Stathmin might be promising targets to improve the cure rates in meningiomas.

MiR-29a is a candidate biomarker of better survival in metastatic high-grade serous carcinoma.

The objective of this study was to analyze the clinical role of 9 microRNAs (miRs) previously found to be overexpressed in ovarian carcinoma effusions compared with primary ovarian carcinomas. High-grade serous carcinoma effusions (n=148) were analyzed for expression of miR-29a, miR-31, miR-99b, miR-182, miR-210, miR-221, miR-222, miR-224, and miR-342 using quantitative polymerase chain reaction. Expression levels were analyzed for association with clinicopathological parameters and survival. miR-29a and miR-31 levels were further assessed for association with protein expression of their targets Stathmin and DNA methyltransferase-3A (DNMT3A) by immunohistochemistry and Western blotting, respectively. miRNA levels were unrelated to clinicopathological parameters. However, higher miR-29a levels were significantly related to longer overall survival in univariate (P=.007) and Cox multivariate survival analysis (P=.045). miR-29a levels were inversely related to those of its target DNMT3A (P=.048), and higher DNMT3A expression was significantly related to poor overall survival in univariate (P=.03) and Cox multivariate (P=.016) survival analysis. In contrast, miR-31 levels were directly related to cytoplasmic phospho-Stathmin expression (P=.029) and unrelated to Stathmin and nuclear phospho-Stathmin, and both Stathmin and phospho-Stathmin expressions were unrelated to survival. miR-29a and its target DNMT3A are novel candidate biomarkers of longer and shorter survival, respectively, in metastatic high-grade serous carcinoma.

Overexpression of stathmin/oncoprotein 18 correlates with poorer prognosis and interacts with p53 in oral squamous cell carcinoma.

PURPOSE: The stathmin/oncoprotein 18 (STMN1) is overexpressed in various human cancers. The aim of our study was to investigate its clinical significance and interaction with p53 in oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Stathmin expression was assessed by Oncomine, Gene Expression Omnibus (GEO) database, western blotting, and reverse transcription polymerase chain reaction. We investigated the relationship between stathmin expression and clinical characteristics among 109 OSCC patients by immunohistochemical staining. The prognosis factors were analyzed using univariate and multivariate analysis. Immunoprecipitation assay and The Cancer Genome Atlas (TCGA) analysis were used to detect the relationship between mutant p53 and stathmin. RESULTS: Stathmin was overexpressed in OSCC. In immunohistochemical analysis, high stathmin expression correlated with gender (P = 0.040), T stage (P = 0.015), TNM stage (P = 0.045), and pathological differentiation (P = 0.000). We found a correlation between the stathmin expression and overall survival (P = 0.027). Multivariate analysis suggested only lymph node metastasis (P = 0.007) and stathmin expression (P = 0.013) as independent prognostic factors. There was interaction between stathmin and p53 in OSCC cell lines with mutant p53 through immunoprecipitation assay. CONCLUSION: These results suggest that overexpression of stathmin could contribute to cancer progression/prognosis, and that interaction between p53 and stathmin may contribute to the gain-of-function of p53.

STMN1 overexpression correlates with biological behavior in human cutaneous squamous cell carcinoma.

Stathmin 1 (STMN1) is an important molecule in regulating cellular microtubule dynamics and promoting microtubule depolymerization in interphase and late mitosis. Evidences showed that STMN1 was up-regulated in many cancers, but there was no report about the roles of STMN1 in human cutaneous squamous cell carcinoma (cSCC). Here, we confirmed significant upregulation of STMN1 in cSCC tissues and cell lines compared with non-tumor counterparts. STMN1 upregulation was associated with the proliferation, migration, invasion and apoptosis of cSCC cells. The results suggested that STMN1 may play an important role in the development and tumor progression of cSCC.