SPI1 activates TGF-ß1/PI3K/Akt signaling through transcriptional upregulation of FKBP12 to support the mesenchymal phenotype of glioma stem cells.

Glioma stem cells (GSCs) exhibit diverse molecular subtypes with the mesenchymal (MES) population representing the most malignant variant. The oncogenic potential of Salmonella pathogenicity island 1 (SPI1), an oncogenic transcription factor, has been established across various human malignancies. In this study, we explored the association between the SPI1 pathway and the MES GSC phenotype. Through comprehensive analysis of the Cancer Genome Atlas and Chinese Glioma Genome Atlas glioma databases, along with patient-derived GSC cultures, we analyzed SPI1 expression. Using genetic knockdown and overexpression techniques, we assessed the functional impact of SPI1 on GSC MES marker expression, invasion, proliferation, self-renewal, and sensitivity to radiation in vitro, as well as its influence on tumor formation in vivo. Additionally, we investigated the downstream signaling cascades activated by SPI1. Our findings revealed a positive correlation between elevated SPI1 expression and the MES phenotype, which in turn, correlated with poor survival. SPI1 enhanced GSC MES differentiation, self-renewal, and radioresistance in vitro, promoting tumorigenicity in vivo. Mechanistically, SPI1 augmented the transcriptional activity of both TGF-ß1 and FKBP12 while activating the non-canonical PI3K/Akt pathway. Notably, inhibition of TGF-ß1/PI3K/Akt signaling partially attenuated SPI1-induced GSC MES differentiation and its associated malignant phenotype. Collectively, our results underscore SPI1's role in activating TGF-ß1/PI3K/Akt signaling through transcriptional upregulation of FKBP12, thereby supporting the aggressive MES phenotype of GSCs. Therefore, SPI1 emerges as a potential therapeutic target in glioma treatment.

PD-L1 and tumor-infiltrating CD8+ lymphocytes are correlated with clinical characteristics in pediatric and adolescent pituitary adenomas.

Objective: To investigate the levels of tumor-infiltrating CD8+ lymphocytes (CD8+ TILs) and the expression of programmed cell death receptor ligand 1 (PD-L1) in the tumor microenvironment (TME) of pediatric and adolescent pituitary adenomas (PAPAs) and analyze the correlation between their levels and the clinical characteristics. Methods: A series of 43 PAPAs cases were enrolled over a period of 5 years. To compare the TME of PAPAs and adult PAs, 43 PAPAs cases were matched with 60 adult PAs cases (30 cases were between 20 and 40 years old, and 30 cases were older than 40 years) for main clinical characteristics. The expression of immune markers in PAPAs was detected by immunohistochemistry, and their correlation with the clinical outcomes was analyzed using statistical methods. Results: In the PAPAs group, CD8+ TILs level was significantly lower (3.4 (5.7) vs. 6.1 (8.5), p = 0.001), and PD-L1 expression (0.040 (0.022) vs. 0.024 (0.024), p < 0.0001) was significantly higher as compared with the older group. The level of CD8+ TILs was negatively correlated with the expression of PD-L1 (r = -0.312, p = 0.042). Moreover, CD8+ TILs and PD-L1 levels were associated with Hardy (CD8, p = 0.014; PD-L1, p = 0.018) and Knosp (CD8, p = 0.02; PD-L1, p = 0.017) classification. CD8+ TILs level was associated with high-risk adenomas (p = 0.015), and it was associated with the recurrence of PAPAs (HR = 0.047, 95% CI 0.003-0.632, p = 0.021). Conclusion: Compared with the TME in adult PAs, the TME in PAPAs was found to express a significantly altered level of CD8+ TILs and PD-L1. In PAPAs, CD8+ TILs and PD-L1 levels were associated with clinical characteristics.

Cancer cell intrinsic TIM-3 induces glioblastoma progression.

Glioblastoma (GBM) is identified to share common signal pathways between glioma and immune cells. Here, we find that T cell immunoglobulin domain and mucin domain protein 3 (TIM-3) is one of the most common co-inhibitory immune checkpoints in GBM shared by tumor and non-tumor cells. Glioma cell-intrinsic TIM-3 is involved in not only regulating malignant behaviors of glioma cells but also inducing macrophage migration and transition to anti-inflammatory/pro-tumorigenic phenotype by a TIM-3/interleukin 6 (IL6) signal. In mechanism, as one of the major regulators of IL6, TIM-3 regulates its expression through activating NF-κB. Blocking this feedback loop by Tocilizumab, an IL6R inhibitor, inhibited the above effects and repressed the tumorigenicity of GBM in vivo. Our work identifies glioma cell-intrinsic functions of TIM-3/IL6 signal mediating the crosstalk feedback loop between glioma cells and tumor-associated macrophages (TAMs). Blocking this feedback loop may provide a novel therapeutic strategy for GBM.

Programmed death ligand 1 and tumor-infiltrating CD8+ T lymphocytes are associated with the clinical features in meningioma.

OBJECTIVE: To investigate the expression of programmed death ligand-1 (PD-L1) and the levels of CD8+ tumor-infiltrating lymphocytes (TILs) in meningioma as well as determine the association between their levels and the clinical outcomes. METHODS: We performed a retrospective case-control study on 93 patients with meningioma. The patients showed tumor recurrence and were matched with the control patients without recurrence in their age, gender, admission time, tumor sites, tumor volume, peritumoral brain edema (PTBE), Simpson grade resection, WHO grade, postoperative radiotherapy, and the follow-up duration. We reviewed the clinical data of patients and performed immunohistochemistry analysis to investigate the PD-L1 expression and the levels of CD8+ TILs. Multivariate logistic regression was performed to analyze the association between clinical features and immune markers. The conditional logistic regression models were used to calculate the odds ratios (ORs) with 95% confidence intervals (CIs), and Kaplan-Meier analysis was performed to analyze tumor recurrence. RESULTS: Tumor volume was correlated with the PD-L1 expression (P = 0.003, HR = 5.288, 95%CI, 1.786-15.651). PTBE served as an independent predictor of CD8+ TIL levels (P = 0.001, HR = 0.176, 95%CI 0.065-0.477). The levels of CD8+ TILs were associated with tumor recurrence (P = 0.020, OR = 0.325, 95%CI, 0.125-0.840). CONCLUSION: Tumor volume was associated with PD-L1 expression, and PTBE was an independent predictor of CD8+ TIL levels in meningioma. CD8+ TIL levels correlated with tumor recurrence in meningioma.

ARHGEF40 promotes non-small cell lung cancer proliferation and invasion via the AKT-Wnt axis by binding to RhoA.

Rho guanine nucleotide exchange factor 40 (ARHGEF40) is a member of the Dbl-family of guanine nucleotide factor proteins. However, its expression pattern and biological function in malignant tumors, notably in nonsmall cell lung cancer (NSCLC) are currently unknown. The present study demonstrated that ARHGEF40 was highly expressed in NSCLC specimens and that its expression was significantly associated with advanced TNM stage (p < 0.001), lymph node metastasis (p = 0.002), and poor prognosis (p = 0.0056). In addition, ARHGEF40 accelerated nuclear translocation of the key component ß-catenin and increased the expression levels of the Wnt signaling pathway targets c-myc, cyclin D1 and MMP7. Moreover, it promoted lung cancer cell proliferation and invasion in vitro and in vivo. To elucidate the underlying molecular mechanism, the current study demonstrated that ARHGEF40 could induce activation of the Wnt signaling pathway by increasing the phosphorylation levels of AKT and GSK3ß via interaction with RhoA. Moreover, the Dbl homology (DH)-pleckstrin homology (PH) domain of ARHGEF40 was responsible for this interaction. Its deletion abolished the binding, which blocked the activation of the Wnt signaling. Taken together, the data indicated that ARHGEF40 promoted the malignant phenotype of lung cancer cells by activating the AKT-Wnt axis. This was achieved by its interaction with RhoA via the DH-PH domain. ARHGEF40 may serve as a novel target for NSCLC treatment.

Coexistence of meningioma and other intracranial benign tumors in non-neurofibromatosis type 2 patients: A case report and review of literature.

BACKGROUND: The coexistence of meningioma and other intracranial primary benign tumors is rare, especially in non-neurofibromatosis type 2, and there is limited guidance for the management of such patients. Here, we report a series of 5 patients with concomitant meningioma and other intracranial benign tumors, including subependymoma and pituitary adenoma. CASE SUMMARY: Five non-neurofibromatosis type 2 patients with simultaneous occurrence of meningioma and other intracranial benign tumors were retrospectively reviewed. The patients had no history of previous irradiation. The clinical features, pre- and postoperative imaging, surgical procedure and pathological findings were extracted from electronic medical records. There were 4 female patients (80%) and 1 male patient (20%). The mean age was 42.8 years (range: 29-52 years). The coexisting tumors included subependymoma in 1 case (20%) and pituitary adenoma in 4 cases (80%). The most common clinical symptom was headache (3/5, 60%). Four patients (80%) underwent craniotomy. One patient (20%) underwent transsphenoidal surgery followed by transcranial operation. All tumor diagnoses were confirmed by histopathological examination. The mean follow-up was 38.8 mo (range: 23-96 mo), and all 5 patients were in a stable condition at the last follow-up. CONCLUSION: The simultaneous occurrence of meningioma and other intracranial benign tumors is a rare clinical event. Histological examination is necessary for the accurate diagnosis. Neurosurgeons should select the appropriate surgical strategy according to the clinical features of each patient, which may provide a more favorable prognosis for individual patients.

Risk Factors of Postoperative Meningitis in Lateral Ventricular Trigone Meningiomas: A Clinical Analysis of 64 Patients.

Purpose: Patients with intraventricular tumors are more susceptible to postoperative meningitis (POM) than other intracranial tumors. In this study, we explored the risk factors of POM in lateral ventricular trigone meningiomas (LVTMs). Methods: Clinical features of 64 patients with LVTMs were analyzed. Age, gender, body mass index, medical history, intraoperative blood loss (IBL), intraventricular drainage placement, surgical duration, tumor grade, postoperative tumor cavity hemorrhage, and tumor size were included in univariate and multivariate analyses of POM. Results: Of the 64 patients, 14 patients (21.9%) received diagnosis of POM. The univariate analysis revealed IBL ≥400 mL (odds ratio [OR], 9.012; p = 0.003), tumor size ≥50 cm3 (OR, 3.071; p = 0.080), and surgical duration ≥5 h (OR, 2.970; p = 0.085) were considered possible risk factors for POM (p < 0.10). Tumor size (R = 0.514) and surgical duration (R = 0.624) were significantly correlated with IBL (p < 0.05). In the multivariate analysis, only IBL was found to be an independent risk factor for POM. Conclusion: The IBL ≥400 mL is independently associated with the increased risk of POM in LVTM patients. Our results demonstrate the importance of controlling IBL for preventing POM, especially in large tumors and long surgeries.

Diffuse midline glioma with H3-K27M mutation: A rare case with GFAP-positive anucleate whorled patterns.

INTRODUCTION: Diffuse midline glioma with H3-K27M mutation is an infiltrative high-grade glioma, with predominantly astrocytic differentiation. PATIENT CONCERNS: A 54-year-old Chinese woman presented with memory loss for a month and walking instability for 15 days. DIAGNOSIS: Magnetic resonance imaging showed a mass shadow of isometric T1 and slightly longer T2 with mild mixed signals in the third ventricle of the suprasellar region. Histologically, the tumor was primarily sheet-like, with many "anucleate areas" composed of long and thin fibrillary processes of the bipolar cells, which formed "whorls." The neoplastic nuclei were ovoid and moderate in size. The tumor showed brisk mitotic activity and vascular proliferation, with no necrosis. In addition to histone H3K27M mutation, immunohistochemical staining showed that the tumor cells were positive for glial fibrillary acidic protein, oligodendrocyte transcription factor 2, alpha-thalassemia/mental retardation syndrome X, S-100 and Vimentin. The "anucleate areas" were positive for glial fibrillary acidic protein and negative for synaptophysin. The Ki-67 proliferation index was about 10%. Molecular genetic analyses detected H3F3A K27M mutation, but no mutations in IDH1 or IDH2, TERT promoter mutations, MGMT promoter methylation, KIAA1549-BRAF fusion or deletion of 1p/19q were found. Based on these findings, the patient was diagnosed as diffuse midline glioma with H3-K27M mutation in the third ventricle, corresponding to WHO grade 4. INTERVENTIONS: A craniotomy with total excision of the tumor was performed. OUTCOMES: After surgery, she was routinely treated with temozolomide for chemotherapy and synchronous radiotherapy. It has been 11 months now, and the patient is living well. CONCLUSION: This case report provides information on the microscopic morphological features of diffuse midline glioma with H3K27M mutation, which can help pathologists to make a definitive diagnosis of this tumor.

Ketamine enhances dopamine D1 receptor expression by modulating microRNAs in a ketamine-induced schizophrenia-like mouse model.

The abnormal expression of the dopamine D1 receptor (DRD1) may be associated with schizophrenia. MicroRNAs (miRNAs) can post-transcriptionally regulate DRD1 expression. Here, we established a ketamine-induced schizophrenia-like behavior mouse model and investigated the changes in miR-15a-3p, miR-15b-3p, miR-16-1-3p, and DRD1 in response to ketamine. Administration of high-dose ketamine for seven consecutive days to mice simulated the main symptoms of schizophrenia. The mice exhibited increasing excitability and autonomous activity and reduced learning and memory, including spatial memory. Moreover, ketamine decreased miR-15a-3p, miR-15b-3p, and miR-16-1-3p expression levels in the prefrontal cortex (PFC) and miR-16-1-3p expression in the hippocampus, whereas DRD1 expression increased in these brain regions. In HT22 mouse hippocampal neuronal cells, ketamine induced a dose-dependent increase of endogenous DRD1, which was partially attenuated by a combination of miR-15b-3p and miR-16-1-3p mimics. Indeed, the miR-15b-3p and miR-16-1-3p mimics could significantly inhibit endogenous DRD1expression. We identified +72 to +78 bp (TGCTGCT) of the DRD1 3'UTR as the core regulatory region recognized by the target miRNAs. In summary, we developed a ketamine-induced schizophrenia-like behavior mouse model and found that ketamine inhibited the levels of miR-15a-3p, miR-15b-3p, miR-16-1-3p and increased DRD1 expression in mice.

Decreased CD8+ Lymphocytic Infiltration in Multifocal and Multicentric Glioblastomas.

PURPOSE: Multifocal and multicentric glioblastomas (mGBMs) are associated with a poorer prognosis compared to unifocal glioblastoma (uGBM). The presence of CD8+ tumor-infiltrating lymphocytes (TILs) is predictive of clinical outcomes in human malignancies. Here, we examined the CD8+ lymphocytic infiltration in mGBMs. METHODS: The clinical data of 57 consecutive IDH wildtype primary mGBM patients with histopathological diagnoses were retrospectively reviewed. CD8+ TILs were quantitatively evaluated by immunohistochemical staining. The survival function of CD8+ TILs was assessed by Kaplan-Meier analysis and Cox proportional hazard models. RESULTS: No significant difference in the concentration of CD8+ TILs was observed among foci from the same patient (P>0.150). The presence of CD8+ TILs was similar between multifocal and multicentric GBMs (P=0.885). The concentration of CD8+ TILs was significantly lower in mGBMs than in uGBMs (P=0.002). In mGBM patients, the CD8+ TIL level was associated with preoperative KPS (P=0.018). The median overall survival (OS) of the 57 mGBMs was 9 months. A low CD8+ TIL level (multivariate HR 4.404, 95% CI 1.954-9.926, P=0.0004) was an independent predictor of poor OS, while postoperative temozolomide chemotherapy (multivariate HR 6.076, 95% CI 2.330-15.842, P=0.0002) was independently associated with prolonged OS in mGBMs. CONCLUSIONS: Decreased CD8+ TIL levels potentially correlate with unfavorable clinical outcome in mGBMs, suggesting an influence of the local immuno-microenvironment on the progression of mGBMs.

Cerebral astroblastoma with oligodendroglial-like cells: A case report.

RATIONALE: Astroblastoma is a rare tumor of the central nervous system with uncertain biological behavior and origin. Its histopathological features have been well established, while, to our knowledge, astroblastoma with oligodendroglial-like cells have not been reported. PATIENT CONCERNS: A 15-year-old girl presented with nausea, vomiting, headache, and visual disturbance. DIAGNOSIS: Magnetic resonance imaging revealed a large neoplasm in the left temporal. Histologically, the tumor showed solid and pseudopapillary structure. Immunohistochemical staining showed that the tumor cells were positive for glial fibrillary acidic protein and vimentin. The oligodendroglial-like cells were positive for glial fibrillary acidic protein, vimentin, and oligodendrocyte transcription factor 2. The antigen KI67 labeling index was about 4%. Sequencing for isocitrate dehydrogenase (IDH) 1 codon 132 and IDH2 codon 172 gene mutations showed negative results. Furthermore, fluorescent analysis revealed neither 1p nor 19q deletion in the lesion. Based on these findings, the girl was finally diagnosed as astroblastoma. INTERVENTIONS: A craniotomy with total excision of the tumor was performed. OUTCOMES: The follow-up time was 1 year, no evidence of disease recurrence was found in magnetic resonance imaging. LESSONS: Cerebral astroblastoma with oligodendroglial-like cells is a clinically rare tumor of central nervous system. Clear distinction and diagnosis are critical.

Supratentorial ependymoma with YAP1:FAM118B fusion: A case report.

We report a case of a 26-year-old Chinese man who had experienced three grand mal seizures in the past two months. Magnetic resonance imaging revealed a relatively well-circumscribed lesion in the left frontal lobe. A craniotomy with total excision of the tumor was performed. Histopathological investigations confirmed a grade 2 ependymoma according to the World Health Organization classification. Genetic analysis revealed a tumor harboring FAM118B fusion to YAP1, and no other genetic alterations or methylation of the O6 -methylguanine-DNA methyltransferase gene promoter were detected. This is the second case report of ependymoma with YAP1:FAM118B fusion.

Metastasis of pulmonary adenocarcinoma to right occipital parafalcine meningioma: A case report and literature review.

RATIONALE: Tumor-to-tumor metastasis is a rare clinical phenomenon. Although meningioma is the most common intracranial recipient of cancer metastasis, only a few cases have been reported. We present a case of metastasis of lung adenocarcinoma into intracranial meningioma and review the published literature. PATIENT CONCERNS: A 70-year-old woman was admitted to our hospital for a 1-month history of headache and pain in her lower extremities. DIAGNOSIS: Brain and lumbar vertebral magnetic resonance imaging showed an intracranial space-occupying lesion in the right occipital region and spinal canal stenosis. Pulmonary computed tomography showed an irregular mass in the right upper lobe of the lung. The postoperative histological examination demonstrated adenocarcinoma metastasis to meningioma. INTERVENTION: The patient underwent right occipital craniotomy for tumor removal and lumbar spinal canal decompression. OUTCOMES: There were no initial abnormal conditions after the operation. However, the patient died suddenly 7 days after surgery. LESSONS: Tumor-to-meningioma metastasis is a rare but important phenomenon. According to previous reports, it is associated with rapid onset of symptoms and a poor prognosis. Histological examination is of great importance in diagnosis. The history and process of malignant carcinoma should be closely monitored.

ANKHD1 promotes proliferation and invasion of non­small­cell lung cancer cells via regulating YAP oncoprotein expression and inactivating the Hippo pathway.

The ankyrin repeat and KH domain­containing 1 (ANKHD1) protein was recently reported to be a potential member of the Hippo signaling pathway. However, its role in human non­small­cell lung cancer (NSCLC) has not been extensively investigated. The aim of the present study was to examine the expression of ANKHD1 in primary human tissues and cells and determine whether it is correlated with the clinical characteristics of tumor growth. The biological functions of ANKHD1 were evaluated in vitro and in vivo. Yes­associated protein (YAP) expression and phosphorylation induced by ANKHD1 were evaluated by western blotting and immunoprecipitation. Marked upregulation of ANKHD1 protein expression was observed in NSCLC cells and tissues, which was associated with advanced pathological tumor­node­metastasis stage, lymph node metastasis and poor prognosis in patients with NSCLC. ANKHD1 overexpression also promoted the proliferation and invasion of NSCLC cells. ANKHD1 upregulation inactivated Hippo signaling via increasing YAP protein levels, as well as inhibiting YAP protein phosphorylation, whereas depletion of YAP abolished the effects of ANKHD1 on cell proliferation and invasion. Therefore, ANKHD1 may play an important role in NSCLC through regulating the YAP­dependent Hippo signaling pathway.

Mixed granulosa-Sertoli sex cord-stromal tumor of the testis: clinical, ultrasonic and histopathological features: a case report.

Testicular sex cord-stromal tumors are less common in men, while mixed sex cord-stromal tumors (MSCSTs) are rarer. Recently, we found a MSCST in an adult male testis [adult granulosa cell tumor (AGCT) with Sertoli cell tumor]. He was admitted to the hospital based on "left testicular bloating and dull pain for 20 years and aggravating for 10 days". Routine examination of color Doppler ultrasound showed a size of approximately 1.09 cm × 0.79 cm in the left testis with a low echo area, clear outline, and color flow in it. The patient underwent a radical left orchiectomy to remove the tumor. Pathological results showed that the tumor was diagnosed as testicular MSCST (AGCT with Sertoli cell tumor). He was in good health after the operation and showed no signs of recurrence or metastasis after 6 months of follow-up. We summarized the clinical, ultrasonic, and histopathological characteristics of this case. And immunohistochemical staining was very important in the pathological diagnosis of testicular MSCSTs, which can distinguish different tumor types. MSCSTs were usually mixed Sertoli-Leydig cell tumors, while this case is a MSCST of AGCT with Sertoli cell tumor, which is unique from other cases. Moreover, in this case, the doctors could not clearly diagnose the tumor through pre-operative physical, ultrasonic and laboratory examinations until the postoperative pathological examination. This further reflected the importance of pathological examination in the diagnosis of such tumors.

Primary low grade myxofibrosarcoma of the liver with benign presentation but malignant outcome: a case report.

BACKGROUND: Myxofibrosarcoma (MFS) is most often found on the limbs of aged male people, but extremely uncommon in the liver. CASE PRESENTATION: A 52-year-old female patient with a liver mass was diagnosed as a primary MFS. It had no obvious abdominal symptoms, and the tumor was resected with an extended margin. Three years after the surgery, the patient was readmitted for peritoneal metastasis and passed away 4 months later. The tumor has a benign presentation, but malignant outcome. CONCLUSIONS: Comprehensive radiological inspection, intensive preoperative evaluation, careful design of operating procedures, wide margin resection, consecutive treatment, and strict periodical follow-ups should be taken to ensure a better prognosis of this kind of neoplastic disease.

Comparative analysis of intracranial meningiomas in patients younger than 40 years.

PURPOSE: Intracranial meningiomas are relatively rare in young adults, and their specific clinical features remain unclear. The authors analyzed the clinical characteristics of intracranial meningioma in patients younger than 40 years. METHODS: Consecutive patients younger than 40 years with meningioma (n = 223) who underwent surgical treatment at our hospital from 2010 to 2018 were retrospectively reviewed. The study cases was further divided into a younger group (≤ 30 years old; n = 63) and an older group (31-40 years old; n = 160). The clinical information, radiological characteristics, intraoperative findings, and pathological outcomes were extracted from the patients' records and statistically analyzed. RESULTS: Intracranial meningioma is uncommon in patients younger than 40 years (8.6%). The study group's most common symptoms at presentation were headaches (46.7%), visual impairment (27.8%), limb weakness (20.6%), and epilepsy (13.5%). The mean tumor size was larger (51.47 ± 50.36 cm3) in the younger group than in the older group (22.94 ± 27.20 cm3). According to multivariate analyses, young age was an independent predictor of large tumor size, and large tumor size was significantly associated with peritumoral brain edema and intraoperative blood loss. CONCLUSION: Intracranial meningiomas in younger adult patients may have special complexity and perioperative risk due to large tumor sizes. Therefore, individualized treatment strategy is recommended, and the appropriate caution should be taken during surgery.

Overexpression of Nemo-like Kinase Promotes the Proliferation and Invasion of Lung Cancer Cells and Indicates Poor Prognosis.

BACKGROUND: Nemo-like kinase (NLK) is an evolutionarily conserved MAP kinaserelated kinase involved in the pathogenesis of several human cancers. OBJECTIVE: The aim of this study was to investigate the expression and role of NLK in lung cancers, and its underlying mechanisms. METHODS: We examined the expression of NLK in lung cancer tissues through western blot analysis. We enhanced or knocked down NLK expression by gene transfection or RNA interference, respectively, in lung cancer cells, and examined expression alterations of key proteins in the Wnt signaling pathway and in epithelial-mesenchymal transition (EMT). We also examined the roles of NLK in the proliferation and invasiveness of lung cancer cells by cell proliferation, colony formation, and Matrigel invasion assays. RESULTS: NLK expression was found to be significantly higher in lung cancer tissue samples than in corresponding healthy lung tissue samples. Overexpression of NLK correlated with poor prognosis of patients with lung cancer. Overexpression of NLK upregulated ß-catenin, TCF4, and Wnt target genes such as cyclin D1, c-Myc, and MMP7. N-cadherin and TWIST, the key proteins in EMT, were upregulated, while E-cadherin expression was reduced. Additionally, proliferation, colony formation, and invasion turned out to be enhanced in NLK-overexpressing cells. After NLK knockdown in lung cancer cells, we obtained the opposite results. CONCLUSION: NLK is overexpressed in lung cancers and indicates poor prognosis. Overexpression of NLK activates the Wnt signaling pathway and EMT and promotes the proliferation and invasiveness of lung cancer cells.

CCDC85B promotes non-small cell lung cancer cell proliferation and invasion.

Coiled-coil domain containing 85 B (CCDC85B) is involved in diverse biological processes; however, its expression patterns and functions in human cancers are yet unknown. The present study demonstrated that the expression of CCDC85B in the cytoplasm of the non-small cell lung cancer (NSCLC) tumor cells was significantly higher compared to adjacent normal lung tissues (P < 0.05). Furthermore, CCDC85B expression correlated with advanced TNM stage (P = 0.004) and positive regional lymph node metastasis (P = 0.009) of NSCLC. In addition, in A549 and H1299 lung cancer cell lines, the overexpression of CCDC85B promoted cell proliferation and invasion, while siRNA-mediated CCDC85B knockdown exhibited opposite effects. CCDC85B promoted AKT and GSK3ß phosphorylation and upregulated the levels of active ß-catenin, Wnt targets c-myc, cyclin D1, and MMP7. Besides, the CCDC85B-induced upregulation of phosphorylated GSK3ß and active ß-catenin was rescued following the treatment with PI3 K inhibitor, LY294002. In conclusion, CCDC85B was associated with NSCLC progression as it promoted the proliferation and invasion of lung cancer cells through activated AKT/GSK3ß/ß-catenin oncogenic signaling pathway. Therefore, CCDC85B might serve as a novel target for NSCLC treatment.

Zinc finger protein 668 suppresses non-small cell lung cancer invasion and migration by downregulating Snail and upregulating E-cadherin and zonula occludens-1.

Zinc finger protein 668 (ZNF668) is a recently discovered protein and its expression levels, as well as its involvement in the invasion and metastasis of non-small cell lung cancer (NSCLC), are largely unknown. In the present study, immunohistochemical analysis demonstrated that ZNF668 protein expression was decreased in lung tumors (51/167, 30.5%) compared with adjacent normal lung tissues (43/62, 69.4%; P<0.001). Subsequent statistical analysis revealed that ZNF668 expression was negatively associated with increased tumor-node-metastasis stage (P=0.019) and lymph node metastasis (P=0.002). Following ZNF668 downregulation by transfection of a ZNF668-expressing plasmid or small interfering RNA, it was demonstrated that ZNF668 inhibited the invasion and migration of NSCLC cells. Furthermore, restoration of ZNF668 expression downregulated the expression of Snail and increased the protein levels of epithelial (E-)cadherin and zonula occludens-1 (ZO-1). The results of the present study suggest that ZNF668 is downregulated in human NSCLC. Furthermore, restoration of ZNF668 expression was demonstrated to decrease the expression of Snail and increase the expression of E-cadherin and ZO-1, suppressing the invasion and migration of NSCLC cells.