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Nuclear clearance and cytoplasmic accumulations of the RNA-binding protein TDP-43 are pathological hallmarks in almost all patients with amyotrophic lateral sclerosis (ALS) and up to 50% of patients with frontotemporal dementia (FTD) and Alzheimers disease. In Alzheimers disease, TDP-43 pathology is predominantly observed in the limbic system and correlates with cognitive decline and reduced hippocampal volume. Disruption of nuclear TDP-43 function leads to abnormal RNA splicing and incorporation of erroneous cryptic exons in numerous transcripts including Stathmin-2 (STMN2, also known as SCG10) and UNC13A, recently reported in tissues from patients with ALS and FTD. Here, we identify both STMN2 and UNC13A cryptic exons in Alzheimers disease patients, that correlate with TDP-43 pathology burden, but not with amyloid-β or tau deposits. We also demonstrate that processing of the STMN2 pre-mRNA is more sensitive to TDP-43 loss of function than UNC13A. In addition, full-length RNAs encoding STMN2 and UNC13A are suppressed in large RNA-seq datasets generated from Alzheimers disease post-mortem brain tissue. Collectively, these results open exciting new avenues to use STMN2 and UNC13A as potential therapeutic targets in a broad range of neurodegenerative conditions with TDP-43 proteinopathy including Alzheimers disease.

Abstract Background Stathmin, a cytosolic microtubule-destabilizing phosphoprotein involved in the regulation of mitosis, is widely expressed in various malignancies and acts as an adverse prognostic factor. Our research analyzed its immunohistochemical expression on a large cohort of ovarian sex cord-stromal tumors, evaluating its potential utility in differential diagnosis, prognosis, and therapeutic application. Methods We examined 390 cases of ovarian sex cord-stromal tumors including 281 adult granulosa cell tumors (AGCT), 5 juvenile granulosa cell tumors (JGCT), 33 Sertoli-Leydig cell tumors (SLCT), 50 fibromas/thecomas (F/T), 11 Leydig cell tumors/steroid cell tumors (LCT/SterCT), 5 sex-cord stromal tumors NOS (SCST-NOS), 3 Sertoli cell tumors (SCT), and 2 sclerosing stromal tumors (ScST). Immunohistochemical analysis was performed using TMAs. Results Strong expression (> 50%) was observed in all cases of AGCT, JGCT, SLCT, SCST-NOS, SCT and 1 ScST. The other case of ScST exhibited mild expression (5–10%). The negative cases included exclusively F/T and LCT/SterCT, with F/T showing 24% of negative cases and LCT/SterCT comprising 64% of negative cases. Conclusion The results of our study indicate that stathmin is neither a prognostic marker nor suitable for the differential diagnosis of challenging cases of ovarian sex cord-stromal tumors. However, its predictive value may be theoretically significant, as a decrease in stathmin expression potentialy influences response to chemotherapy treatment.

Background: Stathmin, a cytosolic microtubule-destabilizing phosphoprotein involved in the regulation of mitosis, is widely expressed in various malignancies and acts as an adverse prognostic factor. Our research analyzed its immunohistochemical expression on a large cohort of ovarian sex cord-stromal tumors, evaluating its potential utility in differential diagnosis, prognosis, and therapeutic application. Methods: We examined 390 cases of ovarian sex cord-stromal tumors including 281 adult granulosa cell tumors (AGCT), 5 juvenile granulosa cell tumors (JGCT), 33 Sertoli-Leydig cell tumors (SLCT), 50 fibromas/thecomas (F/T), 11 Leydig cell tumors/steroid cell tumors (LCT/SterCT), 5 sex-cord stromal tumors NOS (SCST-NOS), 3 Sertoli cell tumors (SCT), and 2 sclerosing stromal tumors (ScST). Immunohistochemical analysis was performed using TMAs. Results: Strong expression (> 50%) was observed in all cases of AGCT, JGCT, SLCT, SCST-NOS, SCT and 1 ScST. The other case of ScST exhibited mild expression (5–10%). The negative cases included exclusively F/T and LCT/SterCT, with F/T showing 24% of negative cases and LCT/SterCT comprising 64% of negative cases. Conclusion: The results of our study indicate that stathmin is neither a prognostic marker nor suitable for the differential diagnosis of challenging cases of ovarian sex cord-stromal tumors. However, its predictive value may be theoretically significant, as a decrease in stathmin expression potentialy influences response to chemotherapy treatment. [ABSTRACT FROM AUTHOR]

Loss of nuclear TDP-43 is a hallmark of neurodegeneration in TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 mislocalization results in cryptic splicing and polyadenylation of pre-messenger RNAs (pre-mRNAs) encoding stathmin-2 (also known as SCG10), a protein that is required for axonal regeneration. We found that TDP-43 binding to a GU-rich region sterically blocked recognition of the cryptic 3 splice site in STMN2 pre-mRNA. Targeting dCasRx or antisense oligonucleotides (ASOs) suppressed cryptic splicing, which restored axonal regeneration and stathmin-2-dependent lysosome trafficking in TDP-43-deficient human motor neurons. In mice that were gene-edited to contain human STMN2 cryptic splice-polyadenylation sequences, ASO injection into cerebral spinal fluid successfully corrected Stmn2 pre-mRNA misprocessing and restored stathmin-2 expression levels independently of TDP-43 binding.

Background: Cancer metastasis is the leading cause of death among cancer patients, but there are numerous treatment options available, including drugs such as albendazole (ABZ) and complementary therapies such as cannabis-based medicines, making them important targets for therapeutic interventions. The present study aimed to assess the impact of ABZ on the protein expression of Tau and Stathmin, as well as cell migration, in patients with metastatic breast cancer (BC), where these proteins play critical roles. Materials and Methods: MCF-7 and MDA-MB-231 cell lines were split into a treatment group that received varying concentrations of a standardized extract of ABZ for 48 hours and a control group that received no treatment in this study. The relative gene expression was measured using a quantitative reverse transcription-real-time polymerase chain reaction assay and the ΔΔct method. A migration assay was also performed to assess cancer metastasis. Results: Tau and Stathmin gene expression and cell migration were significantly decreased compared to the control group. Conclusion: The results of the study demonstrated that ABZ reduced both Tau and Stathmin gene expression, as well as cancer metastasis. Nonetheless, evidence suggests that we can use ABZ as an anti-tumor drug for BC treatment.

BackgroundThe 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.MethodsFifty 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.Resultsp16 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.Conclusionp16 remains superior to both Stathmin-1 and HSP27 in differentiating dysplasia from benign, reactive changes of the cervix.

To analyse the relationship between the Stathmin expression and the tumor immune cell infiltration in primary cervical carcinoma (CC), and its prognostic diagnostic value. Cervical tissue samples from 128 patients admitted to our hospital from February 2021 to February 2022 who underwent hysterectomy or cervical biopsy were selected as the observation objects, and then divided into control group (normal cervical tissue specimen, n = 30), cervical intraepithelial neoplasia (CIN) group (CIN neoplasia cervical tissue specimen, n = 30), and cervical cancer group (cervical tissue specimen of cervical cancer lesion, n = 68) according to pathological results. The expression of Stathmin was detected by Immunohistochemistry (IHC). The numbers of infiltrated neutrophils (TINs) were measured by the specific esterase staining. The pathological data of CC patients were collected, and the protein expression of Stathmin was compared with different pathological data. According to the protein expression of Stathmin, the samples were divided into Stathmin positive group and negative group. The infiltration numbers, the levels of CD3+T, CD4+T and CD8+T of TINs were compared in each group, and CD4+/CD8+ were calculated. Kaplan-Meier survival curve was used for the analysis of the relationship between the Stathmin expression and the clinical prognosis in CC. COX analysis was used to determine the factors affecting the prognosis of patients with CC. The proportion of positive expression of cervical tissue Stathmin in CIN group and cervical cancer group was significantly higher than that in the control group, and the proportion of positive expression of cervical tissue Stathmin in cervical cancer group was significantly higher than that in CIN group (P

Introduction: Malignant pleural mesothelioma (MPM) is a neoplasm with dismal prognosis and notorious resistance to the standard therapeutics cisplatin and pemetrexed. Chalcone derivatives are efficacious anti-cancer agents with minimal toxicity and have, therefore, gained pharmaceutical interest. Here, we investigated the efficacy of CIT-026 and CIT-223, two indolyl-chalcones (CITs), to inhibit growth and viability of MPM cells and defined the mechanism by which the compounds induce cell death. Methods: The effects of CIT-026 and CIT-223 were analyzed in five MPM cell lines, using viability, immunofluorescence, real-time cell death monitoring, and tubulin polymerization assays, along with siRNA knockdown. Phospho-kinase arrays and immunoblotting were used to identify signaling molecules that contribute to cell death. Results: CIT-026 and CIT-223 were toxic in all cell lines at sub-micromolar concentrations, in particular in MPM cells resistant to cisplatin and pemetrexed, while normal fibroblasts were only modestly affected. Both CITs targeted tubulin polymerization via (1) direct interaction with tubulin and (2) phosphorylation of microtubule regulators STMN1, CRMP2 and WNK1. Formation of aberrant tubulin fibers caused abnormal spindle morphology, mitotic arrest and apoptosis. CIT activity was not reduced in CRMP2-negative and STMN1-silenced MPM cells, indicating that direct tubulin targeting is sufficient for toxic effects of CITs. Discussion: CIT-026 and CIT-223 are highly effective inducers of tumor cell apoptosis by disrupting microtubule assembly, with only modest effects on nonmalignant cells. CITs are potent anti-tumor agents against MPM cells, in particular cells resistant to standard therapeutics, and thus warrant further evaluation as potential small-molecule therapeutics in MPM. [ABSTRACT FROM AUTHOR]

Uterine leiomyosarcoma is an aggressive soft tissue tumor. Stathmin, a phosphoprotein that modulates microtubule dynamics, is highly expressed in many malignancies including leiomyosarcoma. The microtubule-depolymerizing agent eribulin has been recently approved for treating malignant soft tissue tumors. Although eribulin inhibits microtubule polymerization, little is known about the relationship between eribulin treatment and stathmin dynamics. In this study, we explored the role of stathmin expression in the action of eribulin in leiomyosarcoma cells. Eribulin induced phosphorylation of stathmin and reduced expression of subunits A and C of protein phosphatase 2A (PP2A) in a leiomyosarcoma cell line. The PP2A activator FTY720 reduced levels of phosphorylated stathmin. Eribulin decreased stathmin protein levels without affecting stathmin mRNA expression. Furthermore, stathmin knockdown attenuated the inhibitory effects of eribulin on cell viability, whereas stathmin overexpression enhanced the anti-proliferative effect of eribulin. Eribulin-resistant leiomyosarcoma cell lines had enhanced expression of the class Ⅰ β-tubulin TUBB1, multi-drug resistance 1 protein MDR1 and breast cancer-resistance protein BCRP, and decreased expression of stathmin. Taken together, these results suggest that stathmin expression modulates the pharmacological efficacy of eribulin in uterine leiomyosarcoma cells.

Loss of nuclear TDP-43 is a hallmark of neurodegeneration in TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 mislocalization results in cryptic splicing and polyadenylation of pre–messenger RNAs (pre-mRNAs) encoding stathmin-2 (also known as SCG10), a protein that is required for axonal regeneration. We found that TDP-43 binding to a GU-rich region sterically blocked recognition of the cryptic 3′ splice site in STMN2 pre-mRNA. Targeting dCasRx or antisense oligonucleotides (ASOs) suppressed cryptic splicing, which restored axonal regeneration and stathmin-2–dependent lysosome trafficking in TDP-43–deficient human motor neurons. In mice that were gene-edited to contain human STMN2 cryptic splice-polyadenylation sequences, ASO injection into cerebral spinal fluid successfully corrected Stmn2 pre-mRNA misprocessing and restored stathmin-2 expression levels independently of TDP-43 binding. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are associated with loss of nuclear transactive response DNA-binding protein 43 (TDP-43). Here we identify that TDP-43 regulates expression of the neuronal growth-associated factor stathmin-2. Lowered TDP-43 levels, which reduce its binding to sites within the first intron of stathmin-2 pre-messenger RNA, uncover a cryptic polyadenylation site whose utilization produces a truncated, non-functional mRNA. Reduced stathmin-2 expression is found in neurons trans-differentiated from patient fibroblasts expressing an ALS-causing TDP-43 mutation, in motor cortex and spinal motor neurons from patients with sporadic ALS and familial ALS with GGGGCC repeat expansion in the C9orf72 gene, and in induced pluripotent stem cell (iPSC)-derived motor neurons depleted of TDP-43. Remarkably, while reduction in TDP-43 is shown to inhibit axonal regeneration of iPSC-derived motor neurons, rescue of stathmin-2 expression restores axonal regenerative capacity. Thus, premature polyadenylation-mediated reduction in stathmin-2 is a hallmark of ALS-FTD that functionally links reduced nuclear TDP-43 function to enhanced neuronal vulnerability.

Objective To study the effect of microtubule depolymerization protein 1 (stathmin, STMN1) on the proliferation and apoptosis of uterine leiomyomas cells under the transcriptional regulation of specialized protein 1 (SP1). Methods A total of 30 patients of uterine leiomyomas undergoing total and subtotal hysterectomy in our hospital from June 2017 to June 2019 were recruited in this study. The mRNA expression levels of STMN1 and SP1 in the uterine leiomyoma tissues and surrounding smooth muscle tissues were detected with qRT-PCR. After STMN1 was knocked down in human uterine leiomyoma (HuLM) cells, CCK8 assay, TUNEL and Western blotting were used to detect the cell proliferation and apoptosis. JASPAR online tool was employed to predict the binding site of transcription factor SP1 and STMN1 promoter. qRT-PCR, Western blotting, luciferase reporter assay, and chromatin immunoprecipitation (ChIP) were applied to verify the transcriptional regulation of SP1 for STMN1, and functional rescue experiments were also carried out. Results The expression levels of STMN1 and SP1 were significantly higher in the uterine leiomyoma tissues than the normal smooth muscle tissues (P < 0.05). Knockdown of STMN1 inhibited the proliferation and promoted the apoptosis in HuLM cells (P < 0.001). SP1, as a transcription factor, positively regulated the expression level of STMN1. Knockdown of SP1 could also inhibit the proliferation and promote the apoptosis of HuLM cells (P < 0.001), and overexpression of STMN1 reversed the effect of knockdown of SP1 on cell proliferation and apoptosis (P < 0.001). Conclusion The transcription factor SP1 promotes the proliferation and inhibits the apoptosis in the uterine leiomyoma cells by up-regulating STMN1.

IntroductionMalignant pleural mesothelioma (MPM) is a neoplasm with dismal prognosis and notorious resistance to the standard therapeutics cisplatin and pemetrexed. Chalcone derivatives are efficacious anti-cancer agents with minimal toxicity and have, therefore, gained pharmaceutical interest. Here, we investigated the efficacy of CIT-026 and CIT-223, two indolyl-chalcones (CITs), to inhibit growth and viability of MPM cells and defined the mechanism by which the compounds induce cell death.MethodsThe effects of CIT-026 and CIT-223 were analyzed in five MPM cell lines, using viability, immunofluorescence, real-time cell death monitoring, and tubulin polymerization assays, along with siRNA knockdown. Phospho-kinase arrays and immunoblotting were used to identify signaling molecules that contribute to cell death.ResultsCIT-026 and CIT-223 were toxic in all cell lines at sub-micromolar concentrations, in particular in MPM cells resistant to cisplatin and pemetrexed, while normal fibroblasts were only modestly affected. Both CITs targeted tubulin polymerization via (1) direct interaction with tubulin and (2) phosphorylation of microtubule regulators STMN1, CRMP2 and WNK1. Formation of aberrant tubulin fibers caused abnormal spindle morphology, mitotic arrest and apoptosis. CIT activity was not reduced in CRMP2-negative and STMN1-silenced MPM cells, indicating that direct tubulin targeting is sufficient for toxic effects of CITs.DiscussionCIT-026 and CIT-223 are highly effective inducers of tumor cell apoptosis by disrupting microtubule assembly, with only modest effects on non-malignant cells. CITs are potent anti-tumor agents against MPM cells, in particular cells resistant to standard therapeutics, and thus warrant further evaluation as potential small-molecule therapeutics in MPM.

In order to assess Stathmin as an immunohistochemical (IHC) indicator of phosphatidylinositol 3-kinase (PI3K) pathway activity in HPV-negative head & neck squamous cell carcinoma (HNSCC), we compared Stathmin IHC to expression of other pathway components. We also evaluated the relationship between Stathmin IHC and the mutational status of four key pathway genes. Finally, we ascertained whether Stathmin IHC correlates with tumor grade or primary site. Correlation exists between high Stathmin expression and high pAKT1 expression, indicating a role for Stathmin IHC as a marker of pathway activity. Our analysis did not show correlation between Stathmin IHC and mutation of the four genes evaluated. We also observed an association between high Stathmin expression and oropharyngeal primary site. Our results suggest utility of Stathmin IHC as an indicator of PI3K pathway activity, and thereby demonstrate potential relevance of Stathmin IHC in the context of HNSCC.

Objective To explore the effect and preliminary mechanism of stathmin on skin fibroblast migration in the early inflammatory reaction of wound healing mimicked by TNF-α stimulation. Methods Human dermal fibroblast was stimulated by TNF-α to establish a cell model of inflammation at the early stage of wound healing. The effect of TNF-α on filopodium formation was observed by immunofluorescence assay, cell migration was detected by scratch wound healing, and stathmin expression level under TNF-α stimulation was measured by immunofluorescence assay and Western blotting. After cytochalasin B stimulation and small interfering RNA were used to interfere stathmin expression, respectively, immunofluorescence assay and scratch wound healing were performed again to observe the changes of filopodia and cell migration. Results TNF-α treatment promoted the formation of filopodia in human dermal fibroblasts, enhanced cell migration (P < 0.05) and increased stathmin expression (P < 0.05). Cytochalasin B treatment reduced the formation of filopodia and cell migration (P < 0.05); and interference of stathmin expression suppressed the formation of filopodia and reduced cell migration (P < 0.05). Conclusion In early inflammation, stathmin mediates skin fibroblast migration by promoting the formation of filopodia.

ObjectiveGynecologic Oncology Group (GOG) 177 demonstrated that addition of paclitaxel to a backbone of adriamycin/cisplatin improves overall survival (OS) and progression-free survival (PFS) for patients with advanced or recurrent endometrial cancer. Using patient specimens from GOG-177, our objective was to identify potential mechanisms underlying the improved clinical response to taxanes. Stathmin (STMN1) is a recognized poor prognostic marker in endometrial cancer that functions as a microtubule depolymerizing protein, allowing cells to transit rapidly through mitosis. Therefore, we hypothesized that one possible mechanism underlying the beneficial effects of paclitaxel could be to counter the impact of stathmin.MethodsWe analyzed the expression of stathmin by immunohistochemistry (IHC) in 69 specimens from patients enrolled on GOG-177. We also determined the correlation between stathmin mRNA expression and clinical outcomes in The Cancer Genome Atlas (TCGA) dataset for endometrial cancer.ResultsWe first established that stathmin expression was significantly associated with shorter PFS and OS for all analyzed cases in both GOG-177 and TCGA. However, subgroup analysis from GOG-177 revealed that high stathmin correlated with poor PFS and OS particularly in patients who received adriamycin/cisplatin only. In contrast, there was no statistically significant association between stathmin expression and OS or PFS in patients treated with paclitaxel/adriamycin/cisplatin.ConclusionsOur findings demonstrate that high stathmin expression is a poor prognostic marker in endometrial cancer. Paclitaxel may help to negate the impact of stathmin overexpression when treating high risk endometrial cancer cases.

Breast cancer is the most common malignant neoplasm among women, responsible for 30% of all malignant tumours, and the second most significant reason of cancer fatality in women. Treatment failure and tumour recurrence are common outcomes of chemotherapy when patients develop multidrug resistance (MDR). New therapeutic methods like molecularly targeted therapeutic interventions need a thorough understanding of malignant tumour's molecular processes. Numerous studies published in the last few years indicate that stathmin and tubulin‐associated units (tau) are upregulated in a range of human malignant tumours, suggesting that they may enhance the incidence and progression of malignancies. By promoting cancer cell reproduction, infiltration and generating drug resistance, these proteins aid in the disease's development. Existing information on the expression of tau protein and stathmin in breast cancer, as well as their involvement in treatment methods, is summarized in this literature review. [ABSTRACT FROM AUTHOR]

Motor neuron diseases (MNDs) are a group of fatal, neurodegenerative disorders with different etiology, clinical course and presentation, caused by the loss of upper and lower motor neurons (MNs). MNs are highly specialized cells equipped with long, axonal processes; axonal defects are some of the main players underlying the pathogenesis of these disorders. Microtubules are key components of the neuronal cytoskeleton characterized by dynamic instability, switching between rapid polymerization and shrinkage. Proteins of the stathmin family affect microtubule dynamics regulating the assembly and the dismantling of tubulin. Stathmin-2 (STMN2) is one of the most abundantly expressed genes in MNs. Following axonal injury, STMN2 expression is upregulated, and the protein is transported toward the growth cones of regenerating axons. STMN2 has a critical role in axonal maintenance, and its dysregulation plays an important role in neurodegenerative processes. Stathmin-1 (STMN1) is a ubiquitous protein that is highly expressed during the development of the nervous system, and its phosphorylation controls microtubule dynamics. In the present review, we summarize what is currently known about the involvement of stathmin alterations in MNDs and the potential therapeutic effect of their modulation, with a specific focus on the most common forms of MND, amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). [ABSTRACT FROM AUTHOR]

The dermal fibroblast is a crucial executor involved in wound healing, and lipopolysaccharide is a key factor in initiating the migration and proliferation of the dermal fibroblasts, followed by wound healing. However, the underlying molecular mechanism is still unknown. In this study, we demonstrated that stathmin increased concomitantly with p38/MAPK pathway activation by lipopolysaccharide stimulation of the human dermal fibroblast (HDF), which induced microtubule (MT) depolymerization followed by increased HDF migration and proliferation. In contrast, the application of taxol, the small interfering RNA transfection of stathmin, or the application of the p38/MAPK inhibitor SB203580 suppressed MT depolymerization and HDF migration and proliferation. Additionally, the overexpression of a MKK6(Glu) mutant, which constitutively activated p38/MAPK, resulted in MT depolymerization and, subsequently, promoted HDF migration and proliferation. Our data reveal a crucial role of stathmin in HDF migration and proliferation. These findings will provide new targets and strategies for clinical interventions in wound healing. [ABSTRACT FROM AUTHOR]

Our previous study found that microRNA-21a-5p (miR-21a-5p) knockdown could improve the recovery of motor function after spinal cord injury in a mouse model, but the precise molecular mechanism remains poorly understood. In this study, a modified Allen’s weight drop was used to establish a mouse model of spinal cord injury. A proteomics approach was used to understand the role of differential protein expression with miR-21a-5p knockdown, using a mouse model of spinal cord injury without gene knockout as a negative control group. We found that after introducing miR-21a-5p knockdown, proteins that played an essential role in the regulation of inflammatory processes, cell protection against oxidative stress, cell redox homeostasis, and cell maintenance were upregulated compared with the negative control group. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis identified enriched pathways in both groups, such as the oxidative phosphorylation pathway, which is relevant to Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, and cardiac muscle contraction. We also found that miR-21a-5p could be a potential biomarker for amyotrophic lateral sclerosis, as miR-21a-5p becomes deregulated in this pathway. These results indicate successful detection of some important proteins that play potential roles in spinal cord injury. Elucidating the relationship between these proteins and the recovery of spinal cord injury will provide a reference for future research of spinal cord injury biomarkers. All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of Shandong University of China on March 5, 2014.

The dermal fibroblast is a crucial executor involved in wound healing, and lipopolysaccharide is a key factor in initiating the migration and proliferation of the dermal fibroblasts, followed by wound healing. However, the underlying molecular mechanism is still unknown. In this study, we demonstrated that stathmin increased concomitantly with p38/MAPK pathway activation by lipopolysaccharide stimulation of the human dermal fibroblast (HDF), which induced microtubule (MT) depolymerization followed by increased HDF migration and proliferation. In contrast, the application of taxol, the small interfering RNA transfection of stathmin, or the application of the p38/MAPK inhibitor SB203580 suppressed MT depolymerization and HDF migration and proliferation. Additionally, the overexpression of a MKK6(Glu) mutant, which constitutively activated p38/MAPK, resulted in MT depolymerization and, subsequently, promoted HDF migration and proliferation. Our data reveal a crucial role of stathmin in HDF migration and proliferation. These findings will provide new targets and strategies for clinical interventions in wound healing.

Background: Triple-negative breast cancer (TNBC) is a category of breast cancer characterized with high molecular heterogeneity. Owing to the lack of effective therapeutic strategies, patients with TNBC have a poor prognosis. Paris saponin VII (PSⅦ), a steroidal saponin extracted from the rhizome of Trichillium tschonoskii Maxim, exhibits excellent anti-cancer activity in a variety of solid tumors. However, the role and potential mechanism of PSⅦ against TNBC remain unexplored., Purpose: This study aimed to elucidate the therapeutic effects of PSⅦ against TNBC and explore the potential mechanism of action., Methods: We combined the analysis of public single-cell sequencing data with weighted gene co-expression network analysis (WGCNA) to identity differentially expressed genes (DEGs) that distinguished malignant and normal epithelial cells in TNBC. Subsequently, the biological features of DEGs in TNBC were evaluated. Gene set enrichment analysis (GSEA) was used to define potential pathways associated with the DEGs. The pharmacological activity of PSⅦ for TNBC was evidenced via in vitro and in vivo experiments, and molecular docking, molecular dynamics (MD), surface plasmon resonance (SPR) assay and western blotting were employed to confirm the relative mechanisms., Results: Single-cell sequencing and WGCNA revealed STMN1 as a pivotal biomarker of TNBC. STMN1 overexpression in TNBC was associated with poor patient prognosis. GSEA revealed a significant accumulation of STMN1 within the MAPK signaling pathway. Furthermore, In vitro experiments showed that PSⅦ showed significantly suppressive actions on the proliferation, migration and invasion abilities for TNBC cells, while inducing apoptosis. Molecular docking, MD analysis and SPR assay indicated a robust interaction between PSⅦ and the MEK protein. Western blotting revealed that PSⅦ may inhibit tumor progression by suppressing the phosphorylation of MEK1/2 and the downstream phosphorylation of ERK1/2 and STMN1. Intraperitoneal injection of PSⅦ (10 mg/kg) notably reduced tumor growth by 71.26 % in a 4T1 xenograft model., Conclusion: In our study, the systems biology method was used to identify potential therapeutic targets for TNBC. In vitro and in vivo experiments demonstrated PSⅦ suppresses cancer progression by targeting the MEK/ERK/STMN1 signaling axis. For the first time, the inhibition of STMN1 phosphorylation has been indicated as a possible mechanism for the anticancer effects of PSⅦ. These results emphasize the potential value of PSⅦ as a promising anti-cancer drug candidate for further development in the field of TNBC therapeutics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Shandong Second Medical University. Published by Elsevier GmbH.. All rights reserved.)

It has long been thought that microtubule disassembly, one of the earliest cellular events, contributes to neuronal pruning and neurodegeneration in development and disease. However, how microtubule disassembly drives neuronal pruning remains poorly understood. Here, we conduct a systematic investigation of various microtubule‐destabilizing factors and identify exchange factor for Arf6 (Efa6) and Stathmin (Stai) as new regulators of dendrite pruning in ddaC sensory neurons during Drosophila metamorphosis. We show that Efa6 is both necessary and sufficient to regulate dendrite pruning. Interestingly, Efa6 and Stai facilitate microtubule turnover and disassembly prior to dendrite pruning without compromising the minus‐end‐out microtubule orientation in dendrites. Moreover, our pharmacological and genetic manipulations strongly support a key role of microtubule disassembly in promoting dendrite pruning. Thus, this systematic study highlights the importance of two selective microtubule destabilizers in dendrite pruning and substantiates a causal link between microtubule disassembly and neuronal pruning. Synopsis: Systematic investigation of microtubule‐destabilizing factors identifies Efa6 and Stathmin as two new regulators of dendrite pruning in Drosophila sensory neurons. Genetic and pharmacological manipulations reveal a causal link between microtubule disassembly and neuronal pruning. A systematic investigation of microtubule‐destabilizing factors reveals important roles of Exchange factor for Arf6 (Efa6) and Stathmin (Stai) in dendrite pruning of ddaC neurons.Efa6 and Stai promote dendrite pruning via facilitating microtubule depolymerization and turnover.Multiple lines of pharmacological and genetic evidence demonstrate a causative role of microtubule disassembly in driving dendrite pruning. [ABSTRACT FROM AUTHOR]

ObjectiveTo credential Stathmin 1 (STMN1) and p16(INK4A) (p16) as adjunct markers for the diagnosis of serous tubal intraepithelial carcinoma (STIC), and to compare STMN1 and p16 expression in p53-positive and p53-negative STIC and invasive high-grade serous carcinoma (HGSC).MethodsImmunohistochemistry (IHC) was used to examine STMN1 and p16 expression in fallopian tube specimens (n=31) containing p53-positive and p53-negative STICs, invasive HGSCs, and morphologically normal FTE (fallopian tube epithelium). STMN1 and p16 expression was scored semiquantitatively by four individuals. The semiquantitative scores were dichotomized, and reported as positive or negative. Pooled siRNA was used to knockdown p53 in a panel of cell lines derived from immortalized FTE and HGSC.ResultsSTMN1 and p16 were expressed in the majority of p53-positive and p53-negative STICs and concomitant invasive HGSCs, but only scattered positive cells were present in morphologically normal FTE. Both proteins were expressed consistently across multiple STICs from the same patient and in concomitant invasive HGSC. Knockdown of p53 in immortalized FTE cells and in four HGSC-derived cell lines expressing different missense p53 mutations did not affect STMN1 protein levels.ConclusionsThis study demonstrates that STMN1 and p16 are sensitive and specific adjunct biomarkers that, when used with p53 and Ki-67, improve the diagnostic accuracy of STIC. The addition of STMN1 and p16 helps to compensate for practical limitations of p53 and Ki-67 that complicate the diagnosis in up to one third of STICs.

Small molecules that bind to tubulin exert powerful effects on cell division and apoptosis (programmed cell death). Cell-based high-throughput screening combined with chemo/bioinformatic and biochemical analyses recently revealed a novel compound MI-181 as a potent mitotic inhibitor with heightened activity towards melanomas. MI-181 causes tubulin depolymerization, activates the spindle assembly checkpoint arresting cells in mitosis, and induces apoptotic cell death. C2 is an unrelated compound previously shown to have lethal effects on microtubules in tumorigenic cell lines. We report 2.60 Å and 3.75 Å resolution structures of MI-181 and C2, respectively, bound to a ternary complex of αβ-tubulin, the tubulin-binding protein stathmin, and tubulin tyrosine ligase. In the first of these structures, our crystallographic results reveal a unique binding mode for MI-181 extending unusually deep into the well-studied colchicine-binding site on β-tubulin. In the second structure the C2 compound occupies the colchicine-binding site on β-tubulin with two chemical moieties recapitulating contacts made by colchicine, in combination with another system of atomic contacts. These insights reveal the source of the observed effects of MI-181 and C2 on microtubules, mitosis, and cultured cancer cell lines. The structural details of the interaction between tubulin and the described compounds may guide the development of improved derivative compounds as therapeutic candidates or molecular probes to study cancer cell division.

The intrinsically disordered protein (IDP) stathmin plays an important regulatory role in cytoskeletal maintenance through its helical binding to tubulin and microtubules. However, it lacks a stable fold in the absence of its binding partner. Although stathmin has been a focus of research over the past two decades, the solution-phase conformational dynamics of this IDP are poorly understood. It has been reported that stathmin is purely monomeric in solution and that it bears a short helical region of persistent foldedness, which may act to nucleate helical folding in the C-terminal direction. Here we report a comprehensive study of the structural equilibria local to this region in stathmin that contradicts these two claims. Using the technique of electron paramagnetic resonance (EPR) spectroscopy on spin-labeled stathmin mutants in the solution-phase and when immobilized on Sepharose solid support, we show that all sites in the helical nucleation region of stathmin exhibit multiple spectral components that correspond to dynamic states of differing mobilities and stabilities. Importantly, a state with relatively low mobility dominates each spectrum with an average population greater than 50%, which we suggest corresponds to an oligomerized state of the protein. This is in contrast to a less populated, more mobile state, which likely represents a helically folded monomeric state of stathmin, and a highly mobile state, which we propose is the random coil conformer of the protein. Our interpretation of the EPR data is confirmed by further characterization of the protein using the techniques of native and SDS PAGE, gel filtration chromatography, and multiangle and dynamic light scattering, all of which show the presence of oligomeric stathmin in solution. Collectively, these data suggest that stathmin exists in a diverse equilibrium of states throughout the purported helical nucleation region and that this IDP exhibits a propensity toward oligomerization.

Abstract Stathmin, a phosphoprotein that modulates microtubule dynamics, is highly expressed in breast cancer cells. Eribulin, a microtubule‐depolymerizing agent, is used to treat patients with advanced breast cancer. However, the detailed mechanisms underlying the action of eribulin during microtubule catastrophe, and the interaction between eribulin and stathmin dynamics, remain unclear. Here, we investigated the role of stathmin in the antiproliferative activity of eribulin in breast cancer cells. Eribulin induced phosphorylation of stathmin in MCF7 and MDA‐MB‐231 cells; this was attenuated by an inhibitor of protein kinase A (H89) and an inhibitor of Ca2+/calmodulin‐dependent kinase II (KN62). In addition, expression of phosphorylated stathmin was reduced by the protein phosphatase PP2A activator FTY720 but increased by the PP2A inhibitor okadaic acid. Of note, expression of PP2A subunits in eribulin‐treated cells decreased, although eribulin did not affect the phosphatase activity of recombinant PP2A directly. Furthermore, the antiproliferative effect of eribulin was stronger in stathmin‐overexpressing cells. These results suggest that stathmin dynamics are closely associated with the antiproliferative effects of eribulin and stathmin is a possible biomarker for predicting the therapeutic effects of eribulin in breast cancer patients.

A precise sequence of axon guidance events is required for the development of the ocular motor system. Three cranial nerves grow toward, and connect with, six extraocular muscles in a stereotyped pattern, to control eye movements. The signaling protein alpha2-chimaerin (a2-CHN) plays a pivotal role in the formation of the ocular motor system; mutations in CHN1, encoding a2-CHN, cause the human eye movement disorder Duane Retraction Syndrome (DRS). Our research has demonstrated that the manipulation of a2-chn signaling in the zebrafish embryo leads to ocular motor axon wiring defects, although the signaling cascades regulated by a2-chn remain poorly understood. Here, we demonstrate that several cytoskeletal regulatory proteins--collapsin response mediator protein 2 (CRMP2; encoded by the gene dpysl2), stathmin1, and stathmin 2--bind to a2-CHN. dpysl2, stathmin1, and especially stathmin2 are expressed by ocular motor neurons. We find that the manipulation of dpysl2 and of stathmins in zebrafish larvae leads to defects in both the axon wiring of the ocular motor system and the optokinetic reflex, impairing horizontal eye movements. Knockdowns of these molecules in zebrafish larvae of either sex caused axon guidance phenotypes that included defasciculation and ectopic branching; in some cases, these phenotypes were reminiscent of DRS. chn1 knock-down phenotypes were rescued by the overexpression of CRMP2 and STMN1, suggesting that these proteins act in the same signaling pathway. These findings suggest that CRMP2 and stathmins signal downstream of a2-CHN to orchestrate ocular motor axon guidance and to control eye movements. [ABSTRACT FROM AUTHOR]

CARD-containing MAGUK protein 3 (CARMA3) is associated with tumor occurrence and progression. However, the signaling pathways involved in CARMA3 function remain unclear. We aimed to analyze the association between CARMA3 and stathmin (STMN1) through the NF-κB pathway, which is associated with cell proliferation and invasion, in clear cell renal cell carcinoma (ccRCC). We evaluated the effects of CARMA3 and STMN1 expression on cell migration, proliferation, and invasion in various cell lines, and their expression in tissue samples from patients with ccRCC. CARMA3 was highly expressed in ccRCC tissues and cell lines. Moreover, CARMA3 promoted the proliferation and invasion of RCC cells by activating the NF-κB pathway to transcribe STMN1. Stathmin exhibited a consistent profile with CARMA3 in ccRCC tissue, and could be an effector for CARMA3-activated cell proliferation and invasion of ccRCC cells. In summary, CARMA3 may serve as a promising target for ccRCC treatment. [ABSTRACT FROM AUTHOR]

[Display omitted] Paclitaxel is widely used to treat cancer, however, drug resistance limits its clinical utility. STAT3 is constitutively activated in some cancers, and contributes to chemotherapy resistance. Currently, several STAT3 inhibitors including WP1066 are used in cancer clinical trials. However, whether WP1066 reverses paclitaxel resistance and the mechanism remains unknown. Here, we report that in contrast to paclitaxel-sensitive parental cells, the expressions of several pro-survival BCL2 family members such as BCL-2, BCL-XL and MCL-1 are higher in paclitaxel-resistant ovarian cancer cells. Meanwhile, STAT3 is constitutively activated while stathmin loses its activity in paclitaxel-resistant cells. Importantly, WP1066 amplifies the inhibition of cell proliferation, colony-forming ability and apoptosis of ovarian cancer cells induced by paclitaxel. Mechanistically, WP1066, on the one hand, interferes the STAT3/Stathmin interaction, causing unleash of STAT3/Stathmin from microtubule, thus destroying microtubule stability. This process results in reduction of Ac-α-tubulin, further causing MCL-1 reduction. On the other hand, WP1066 inhibits phosphorylation of STAT3 by JAK2, and blocks its nuclear translocation, therefore repressing the transcription of pro-survival targets such as BCL-2, BCL-XL and MCL-1. Finally, the two pathways jointly promote cell death. Our findings reveal a new mechanism wherein WP1066 reverses paclitaxel-resistance of ovarian cancer cells by dually inhibiting STAT3 activity and STAT3/Stathmin interaction, which may lay foundation for WP1066 combined with paclitaxel in treating paclitaxel-resistant ovarian cancer. [ABSTRACT FROM AUTHOR]

Although testicular germ cell tumors are generally quite responsive to treatment with cisplatin, a small fraction of them acquire resistance during therapy. Even when cisplatin treatment is successful the patient is often left with a residual teratoma at the site of the primary tumor suggesting that cisplatin may trigger differentiation in some tumors. Using the human embryonal carcinoma cell line NTera2/D1, we confirmed that exposure to the differentiating agent retinoic acid produced a reduction in pluripotency markers NANOG and POU5F1 (Oct3/4) and an acute concentration-dependent increase in resistance to both cisplatin and paclitaxel that reached as high as 18-fold for cisplatin and 61-fold for paclitaxel within four days. A two day exposure to cisplatin also produced a concentration-dependent decrease in the expression of the NANOG and POU5F1 and increased expression of three markers whose levels increase with differentiation including Nestin, SCG10 and Fibronectin. In parallel, exposure to cisplatin induced up to 6.2-fold resistance to itself and 104-fold resistance to paclitaxel. Paclitaxel did not induce differentiation or resistance to either itself or cisplatin. Neither retinoic acid nor cisplatin induced resistance in cervical or prostate cancer cell lines or other germ cell tumor lines in which they failed to alter the expression of NANOG and POU5F1. Forced expression of NANOG prevented the induction of resistance to cisplatin by retinoic acid. We conclude that cisplatin can acutely induce resistance to itself and paclitaxel by triggering a differentiation response in pluripotent germ cell tumor cells.

Abstract Background Members of the karyopherin superfamily serve as nuclear transport receptors/adaptor proteins and provide exchange of macromolecules between the nucleo- and cytoplasm. Emerging evidence suggests a subset of karyopherins to be dysregulated in hepatocarcinogenesis including karyopherin-α2 (KPNA2). However, the functional and regulatory role of KPNA2 in liver cancer remains incompletely understood. Methods Quantitative proteomics (LC-MS/MS, ~ 1750 proteins in total) was used to study changes in global protein abundance upon siRNA-mediated KPNA2 knockdown in HCC cells. Functional and mechanistic analyses included colony formation and 2D migration assays, co-immunoprecipitation (CoIP), chromatin immunoprecipitation (ChIP), qRT-PCR, immmunblotting, and subcellular fractionation. In vitro results were correlated with data derived from a murine HCC model and HCC patient samples (3 cohorts, n > 600 in total). Results The proteomic approach revealed the pro-tumorigenic, microtubule (MT) interacting protein stathmin (STMN1) among the most downregulated proteins upon KPNA2 depletion in HCC cells. We further observed that KPNA2 knockdown leads to reduced tumor cell migration and colony formation of HCC cells, which could be phenocopied by direct knockdown of stathmin. As the underlying regulatory mechanism, we uncovered E2F1 and TFDP1 as transport substrates of KPNA2 being retained in the cytoplasm upon KPNA2 ablation, thereby resulting in reduced STMN1 expression. Finally, murine and human HCC data indicate significant correlations of STMN1 expression with E2F1/TFPD1 and with KPNA2 expression and their association with poor prognosis in HCC patients. Conclusion Our data suggest that KPNA2 regulates STMN1 by import of E2F1/TFDP1 and thereby provide a novel link between nuclear transport and MT-interacting proteins in HCC with functional and prognostic significance.

Abstract The p27kip1 protein, mainly known as a negative regulator of cell proliferation, has also been involved in the control of other cellular processes, including the regulation of cytoskeleton dynamics. Notably, these two functions involve distinct protein domains, residing in the N- and C-terminal halves, respectively. In the last two decades, p27kip1 has been reported to interact with microtubule and acto-myosin cytoskeletons, both in direct and indirect ways, overall drawing a picture in which several factors play their role either in synergy or in contrast one with another. As a result, the role of p27kip1 in cytoskeleton dynamics has been implicated in cell migration, both in physiologic and in neoplastic contexts, modulating cytokinesis, lipid raft trafficking, and neuronal development. Recently, two distinct papers have further reported a central role for p27kip1 in the control of microtubule stability and post-translational modifications, dissecting the interaction between p27kip1 and α-tubulin-acetyl-transferase (α-TAT), an enzyme involved in the stability of microtubules, and protein-regulator of cytokinesis 1 (PRC1), a nuclear regulator of the central spindle during mitosis. In light of these recent evidences, we will comment on the role of p27kip1 on cytoskeleton regulation and its implication for cancer progression.

Regulation of microtubule dynamic instability is crucial for cellular processes, ranging from mitosis to membrane transport. Stathmin (also known as oncoprotein 18/Op18) is a prominent microtubule destabilizer that acts preferentially on microtubule minus ends. Stathmin has been studied intensively because of its association with multiple types of cancer, but its mechanism of action remains controversial. Two models have been proposed. One model is that stathmin promotes microtubule catastrophe indirectly, and does so by sequestering tubulin; the other holds that stathmin alters microtubule dynamics by directly destabilizing growing microtubules. Stathmin's sequestration activity is well established, but the mechanism of any direct action is mysterious because stathmin binds to microtubules very weakly. To address these issues, we have studied interactions between stathmin and varied tubulin polymers. We show that stathmin binds tightly to Dolastatin-10 tubulin rings, which mimic curved tubulin protofilaments, and that stathmin depolymerizes stabilized protofilament-rich polymers. These observations lead us to propose that stathmin promotes catastrophe by binding to and acting upon protofilaments exposed at the tips of growing microtubules. Moreover, we suggest that stathmin's minus-end preference results from interactions between stathmin's N terminus and the surface of α-tubulin that is exposed only at the minus end. Using computational modeling of microtubule dynamics, we show that these mechanisms could account for stathmin's observed activities in vitro, but that both the direct and sequestering activities are likely to be relevant in a cellular context. Taken together, our results suggest that stathmin can promote catastrophe by direct action on protofilament structure and interactions.

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Background and Objectives: Stathmin is a phosphoprotein, which in its phosphorylated/unphosphorylated states plays a major role in polymerization/depolymerization of microtubules, respectively. Assembly of microtubules is an important aspect of cell division called mitosis. Hinderance in the function of stathmin could lead to damage in the mitotic process resulting in aneuploidy which is common manifestation of malignancies. Hence, stathmin could be used as a tumor marker for oral dysplasias and cancers. The purpose of the study is to compare the expression of stathmin in normal subjects to the patients with oral leukoplakia and to correlate its expression with different histopathological grades of oral leukoplakia This is the first ever study conducted to examine the expression of stathmin in oral dysplasia. Methodology: Thirty histopathologically confirmed cases of oral dysplasia were selected for the study. These tissues were evaluated immunohistochemically for stathmin. To enumerate the stathmin stained cells, 300 cells were examined manually in at least 5 areas and a mean percentage of positive–stained slides were determined. Then, each sample was assigned to one of the following staining scores: (0) – (<10% of stained cells); (1) – (11%–25% of stained cells); (2) – (26%–50% of stained cells); (3) – (51%–75% of stained cells); (4) – (76%–90% of stained cells) and (5) – (91%–100% of stained cells). The results were analyzed statistically using ANNOVA test. Results: When comparison was made with respect to staining scores of stathmin between normal and dysplasia groups, the results were found to be statistically significant with a P = 0.0001. A statistically significant difference was observed between various histopathological grades of dysplasia with respect to stathmin immunohistochemistry scores with a P = 0.0001. Conclusion: These results suggest stathmin as a tumor marker and prognostic indicator. [ABSTRACT FROM AUTHOR]

Statins are the most effective therapeutic agents for reducing cholesterol synthesis. Given their widespread use, many adverse effects from statins have been reported; of these, musculoskeletal complications occurred in 15% of patients after receiving statins for 6 months, and simvastatin was the most commonly administered statin among these cases. This study investigated the negative effects of simvastatin on skeletal muscle cells. We performed RNA sequencing analysis to determine gene expression in simvastatin-treated cells. Cell proliferation and migration were examined through cell cycle analysis and the transwell filter migration assay, respectively. Cytoskeleton rearrangement was examined through F-actin and tubulin staining. Western blot analysis was performed to determine the expression of cell cycle-regulated and cytoskeleton-related proteins. Transfection of small interfering RNAs (siRNAs) was performed to validate the role of cofilin and stathmin in the simvastatin-mediated inhibition of cell migration. The results revealed that simvastatin inhibited the proliferation and migration of skeletal muscle cells and affected the rearrangement of F-actin and tubulin. Simvastatin reduced the expression of cofilin and stathmin. The knockdown of both cofilin and stathmin by specific siRNA synergistically impaired cell migration. In conclusion, our results indicated that simvastatin inhibited skeletal muscle cell migration by reducing the expressions of cofilin and stathmin.

Motor neuron diseases (MNDs) are a group of fatal, neurodegenerative disorders with different etiology, clinical course and presentation, caused by the loss of upper and lower motor neurons (MNs). MNs are highly specialized cells equipped with long, axonal processes; axonal defects are some of the main players underlying the pathogenesis of these disorders. Microtubules are key components of the neuronal cytoskeleton characterized by dynamic instability, switching between rapid polymerization and shrinkage. Proteins of the stathmin family affect microtubule dynamics regulating the assembly and the dismantling of tubulin. Stathmin-2 (STMN2) is one of the most abundantly expressed genes in MNs. Following axonal injury, STMN2 expression is upregulated, and the protein is transported toward the growth cones of regenerating axons. STMN2 has a critical role in axonal maintenance, and its dysregulation plays an important role in neurodegenerative processes. Stathmin-1 (STMN1) is a ubiquitous protein that is highly expressed during the development of the nervous system, and its phosphorylation controls microtubule dynamics. In the present review, we summarize what is currently known about the involvement of stathmin alterations in MNDs and the potential therapeutic effect of their modulation, with a specific focus on the most common forms of MND, amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA).

Human papillomavirus (HPV) is the leading cause of cervical cancer and has been implicated in several other cancer types including vaginal, vulvar, penile, and oropharyngeal cancers. Despite the recent availability of a vaccine, there are still over 310,000 deaths each year worldwide. Current treatments for HPV-mediated cancers show limited efficacy, and would benefit from improved understanding of disease mechanisms. Recently, we developed a Drosophila 'HPV 18 E6' model that displayed loss of cellular morphology and polarity, junctional disorganization, and degradation of the major E6 target Magi; we further provided evidence that mechanisms underlying HPV E6-induced cellular abnormalities are conserved between humans and flies. Here, we report a functional genetic screen of the Drosophila kinome that identified IKK β —a regulator of NF-κB—as an enhancer of E6-induced cellular defects. We demonstrate that inhibition of IKK β reduces Magi degradation and that this effect correlates with hyperphosphorylation of E6. Further, the reduction in IKK β suppressed the cellular transformation caused by the cooperative action of HPVE6 and the oncogenic Ras. Finally, we demonstrate that the interaction between IKK β and E6 is conserved in human cells: inhibition of IKK β blocked the growth of cervical cancer cells, suggesting that IKK β may serve as a novel therapeutic target for HPV-mediated cancers. [ABSTRACT FROM AUTHOR]

Background: Liver cancer is one of the deadliest malignant tumors worldwide. Immunotherapy has provided hope to patients with advanced liver cancer, but only a small fraction of patients benefit from this treatment due to individual differences. Identifying immune-related gene signatures in liver cancer patients not only aids physicians in cancer diagnosis but also offers personalized treatment strategies, thereby improving patient survival rates. Although several methods have been developed to predict the prognosis and immunotherapeutic efficacy in patients with liver cancer, the impact of cell-cell interactions in the tumor microenvironment has not been adequately considered., Aim: To identify immune-related gene signals for predicting liver cancer prognosis and immunotherapy efficacy., Methods: Cell grouping and cell-cell communication analysis were performed on single-cell RNA-sequencing data to identify highly active cell groups in immune-related pathways. Highly active immune cells were identified by intersecting the highly active cell groups with B cells and T cells. The significantly differentially expressed genes between highly active immune cells and other cells were subsequently selected as features, and a least absolute shrinkage and selection operator (LASSO) regression model was constructed to screen for diagnostic-related features. Fourteen genes that were selected more than 5 times in 10 LASSO regression experiments were included in a multivariable Cox regression model. Finally, 3 genes (stathmin 1, cofilin 1, and C-C chemokine ligand 5) significantly associated with survival were identified and used to construct an immune-related gene signature., Results: The immune-related gene signature composed of stathmin 1, cofilin 1, and C-C chemokine ligand 5 was identified through cell-cell communication. The effectiveness of the identified gene signature was validated based on experimental results of predictive immunotherapy response, tumor mutation burden analysis, immune cell infiltration analysis, survival analysis, and expression analysis., Conclusion: The findings suggest that the identified gene signature may contribute to a deeper understanding of the activity patterns of immune cells in the liver tumor microenvironment, providing insights for personalized treatment strategies., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Abstract Background Stathmin as a critical protein involved in microtubule polymerization, is necessary for survival of cancer cells. However, extremely little is known about Stathmin in glioblastoma. So, this study was designed to elucidate the function of Stathmin gene in the tumorigenesis and progression of glioblastoma cells. Method The lentiviral interference vector pLV3-si-Stathmin targeting Stathmin gene and the control vector pLV3-NC were established for the co-transfection of 293T cells together with the helper plasmids. Viral titer was determined via limiting dilution assay. Then pLV3-si-Stathmin and pLV3-NC were stably co-transfected into U373 and U87-MG glioblastoma cells. Expression levels of Stathmin protein in each group were determined by using Western Blot, and the proliferation and migration ability of the cells with downregulated Stathmin were evaluated through CCK8 assay and transwell invasion assay, respectively. Cell cycles and cell apoptosis were detected with flow cytometry. Finally, the effect of Stathmin in tumor formation was determined in nude mice. Result DNA sequencing and viral titer assay indicated that the lentiviral interference vector was successfully established with a viral titer of 4 × 108 TU/ml. According to the results from Western Blotting, Stathmin protein expression level decreased significantly in the U373 and U87-MG cells after transfected with pLV3-si-Stathmin, respectively, compared with those transfected with pLV3-NC. In glioblastoma cells, the cell proliferation and migration were greatly inhibited after the downregulation of Stathmin protein. Flow cytometry showed that much more cells were arrested in G2/M phasein Stathmin downregulated group, compared with the non-transfection group and NC group. But Stathmin downregulation did not induce significant cell apoptosis. Tumor formation assay in nude mice showed that tumor formation was delayed after Stathmin downregulation, with a reduction in both tumor formation rate and tumor growth velocity. Conclusion Stathmin downregulation affected the biological behaviors of U373 and U87-MG glioblastoma cells, inhibiting the proliferation and migration of tumor cells. Stathmin gene may serve as a potential target in gene therapy for glioblastoma.

Posttraumatic stress disorder (PTSD) is closely related to brain structures of the memory loop such as the hippocampus, amygdala, and medial prefrontal cortex (mPFC). The fear gene stathmin plays an important role in regulating fear memory. However, whether the fear gene stathmin is related to fear memory loop anomalies caused by PTSD is unclear. A single-prolonged stress (SPS) rat model of PTSD was constructed. Wistar rats were randomly divided into 5 groups: the control group, SPS 1-day group, SPS 4-day group, SPS 7-day group, and SPS 14-day group. Then, we measured the protein and mRNA expression of stathmin, p-stathmin (Ser16, Ser25, Ser38, and Ser63), β-tubulin, and MAP-1B in the hippocampus, amygdala, and mPFC in the 5 groups by immunohistochemistry, Western blotting, and qRT-PCR. The expression of the stathmin protein in the hippocampus, mPFC, and amygdala of the rat memory loop decreased gradually in the SPS 1-day group, the SPS 4-day group, and the SPS 7-day group, in which it was the lowest, and then increased. The trend of the expression of stathmin mRNA in the three areas of the memory loop was consistent with the trend of the expression of the stathmin protein. The trend of the protein expression of p-stathmin (Ser25 and Ser38) was opposite of that of stathmin; it reached a peak on the 7th day, and then decreased in the hippocampus. The protein expression of p-stathmin (Ser63) showed the same trend in the mPFC. The protein and mRNA expression of β-tubulin and MAP-1B was consistent with that of p-stathmin; it reached a peak on the 7th day, and then decreased in the rat hippocampus, mPFC, and amygdala. Stathmin in the memory loop, especially in the hippocampus, regulates microtubule structure through its phosphorylation at Ser25 and Ser38 and thereby participates in the mediation of fear memory abnormalities in PTSD. [ABSTRACT FROM AUTHOR]

The endogenous cellular signals that initiate the transition of hepatocytes from quiescence to proliferation remain unclear. The protein stathmin 1 (STMN1) is highly expressed in dividing cells, including hepatocytes, and functions to promote cell mitosis through physical interactions with tubulin and microtubules that regulate mitotic spindle formation. The recent finding that STMN1 mediates the resistance of cultured hepatocytes to oxidant stress led to an examination of the expression and function of this protein in the liver in vivo. STMN1 messenger RNA (mRNA) and protein were essentially undetectable in normal mouse liver but increased markedly in response to oxidant injury from carbon tetrachloride. Similarly, levels of STMN1 mRNA and protein were increased in human livers from patients with acute fulminant hepatic failure. To determine STMN1 function in the liver in vivo, mice were infected with a control or Stmn1‐expressing adenovirus. Stmn1 expression induced spontaneous liver enlargement with a doubling of the liver to body weight ratio. The increase in liver mass resulted, in part, from hepatocellular hypertrophy but mainly from an induction of hepatocyte proliferation. STMN1 expression led to marked increases in the numbers of 5‐bromo‐2′‐deoxyuridine‐positive and mitotic hepatocytes and hepatic nuclear levels of cyclins and cyclin‐dependent kinases. STMN1‐induced hepatocyte proliferation was followed by an apoptotic response and a return of the liver to its normal mass. Conclusion: STMN1 promotes entry of quiescent hepatocytes into the cell cycle. STMN1 expression by itself in the absence of any reduction in liver mass is sufficient to stimulate a hepatic proliferative response that significantly increases liver mass. [ABSTRACT FROM AUTHOR]