Development of a preoperative index-based nomogram for the prediction of hypokalemia in patients with pituitary adenoma: a retrospective cohort study.

OBJECTIVE: To develop and validate a preoperative index-based nomogram for the prediction of hypokalemia in patients with pituitary adenoma (PA). METHODS: This retrospective cohort study included 205 patients with PAs between January 2013 and April 2020 in the Sun Yat-sen Memorial Hospital, Guangzhou, China. The patients were randomly classified into either a training set (N = 143 patients) and a validation set (N = 62 patients) at a ratio of 7:3. Variables, which were identified by using the LASSO regression model were included for the construction of a nomogram, and a logistic regression analysis was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) in the training set. The area under the curve (AUC) was used to evaluate the performance of the nomogram for predicting hypokalemia. Multivariate logistic regression analysis with a restricted cubic spline analysis was conducted to identify a potential nonlinear association between the preoperative index and hypokalemia. RESULTS: The incidence of hypokalemia was 38.05%. Seven preoperative indices were identified for the construction of the nomogram: age, type of PA, weight, activated partial thromboplastin time, urea, eosinophil percentage, and plateletocrit. The AUCs of the nomogram for predicting hypokalemia were 0.856 (95% CI [0.796-0.915]) and 0.652 (95% CI [0.514-0.790]) in the training and validation sets, respectively. Restricted cubic splines demonstrated that there was no nonlinear association between hypokalemia and the selected variables. CONCLUSION: In this study, we constructed a preoperative indices-based nomogram that can assess the risk of hypokalemia after the surgical treatment of pituitary adenomas. This nomogram may also help to identify high risk patients who require close monitoring of serum potassium.

LncRNA KCNQ1OT1 regulates proliferation and cisplatin resistance in tongue cancer via miR-211-5p mediated Ezrin/Fak/Src signaling.

Numerous findings have demonstrated that long noncoding RNA (lncRNA) dysregulation plays a key role in many human neoplasms, including tongue squamous cell carcinoma (TSCC), yet the potential mechanisms of lncRNAs in chemo-resistance remain elusive. Our research showed that the lncRNA KCNQ1OT1 was upregulated in chemo-insensitive TSCC tissues compared with chemo-sensitive TSCC specimens. Meanwhile, high KCNQ1OT1 expression was closely correlated with poor prognosis. Furthermore, KCNQ1OT1 promoted TSCC proliferation and conferred TSCC resistance to cisplatin-induced apoptosis in vitro and in vivo. Using online database analysis, we predicted that the lncRNA KCNQ1OT1 facilitates tumor growth and chemo-resistance by acting as a competing endogenous RNA (ceRNA) to modulate the expression of miR-211-5p. And miR-211-5p upregulation significantly impaired TSCC proliferation and resumed TSCC chemo-sensitivity, which is contrary to the function of lncRNA KCNQ1OT1. Luciferase experiments confirmed that miR-211-5p harbor binding sites for the 3'-UTRof Ezrin mRNA, and Ezrin/Fak/Src signaling was activated in cisplatin-resistant TSCC cells. Finally, miR-211-5p inhibition in sh-KCNQ1OT1-expressing TSCC cells rescued the suppressed cell proliferation and cisplatin resistance induced by KCNQ1OT1 knockdown. In summary, our study has elucidated the role of the oncogenic lncRNA KCNQ1OT1 in TSCC growth and chemo-resistance, which may serve as a new target for TSCC therapy.

Chemotherapy-Induced Long Non-coding RNA 1 Promotes Metastasis and Chemo-Resistance of TSCC via the Wnt/ß-Catenin Signaling Pathway.

Increasing evidence has shown that chemo-resistance is related to the process of epithelial-mesenchymal transition (EMT) and increased invasiveness by tongue squamous cell carcinoma (TSCC) cells. Long non-coding RNAs (lncRNAs) play pivotal roles in tumor metastasis and progression. However, the roles and mechanisms of lncRNAs in cisplatin-resistance-induced EMT and metastasis are not well understood. In this study, a chemotherapy-induced lncRNA 1 (CILA1) was discovered by using microarrays and was functionally identified as a regulator of chemo-sensitivity in TSCC cells. Upregulation of CILA1 promotes EMT, invasiveness, and chemo-resistance in TSCC cells, whereas the inhibition of CILA1 expression induces mesenchymal-epithelial transition (MET) and chemo-sensitivity, and inhibits the invasiveness of cisplatin-resistant cells both in vitro and in vivo. We also found that CILA1 exerts its functions via the activation of the Wnt/ß-catenin signaling pathway. High CILA1 expression levels and low levels of phosphorylated ß-catenin were closely associated with cisplatin resistance and advanced disease stage, and were predictors of poor prognosis in TSCC patients. These findings provided a new biomarker for the chemo-sensitivity of TSCC tumors and a therapeutic target for TSCC treatment.

Long non-coding RNA HOTTIP promotes hypoxia-induced epithelial-mesenchymal transition of malignant glioma by regulating the miR-101/ZEB1 axis.

Hypoxia is a universal characteristic of solid tumor and involving cancer metastasis via epithelial-mesenchymal transition (EMT). Long non-coding RNAs (lncRNAs) are known to regulate carcinogenesis and metastasis of various cancers. The aim of this study was to identify the function role of lncRNAs in the hypoxia-induced EMT of malignant glioma. We used U87 and U251 cell lines were treated under hypoxia to induce EMT, then lncRNA microarray analyse was performed between U87-hypoxia and parental cell line. The relative expression of lncRNA and HIF-1α were detected by qRT-PCR between glioma tissues without metastasis and that with metastasis. Hypoxia could induce EMT and increase HOTTIP expression in glioma cells. Among the different expressions of lncRNAs, HOTTIP was the most upregulated lncRNA in glioma cells treated by hypoxia. High levels of HOTTIP and HIF-1α were correlated with glioma metastasis and poor patient prognosis. Knockdown of HIF-1α and HOTTIP blocked hypoxia-induced EMT, and suppressed invasion and migration of glioma cells. Finally, HOTTIP sponged endogenous miR-101 and inhibited its activity, which resulted in increased ZEB1 expression and promoted process of EMT. HIF-1α/HOTTIP/miR-101/ZEB1 axis plays essential role in hypoxia-induced EMT and metastasis of glioma, and HOTTIP may serve as a therapeutic target to reverse EMT and prevent glioma progression.

miR-582-5p inhibits invasion and migration of salivary adenoid cystic carcinoma cells by targeting FOXC1.

OBJECTIVE: Neurotropism of salivary adenoid cystic carcinoma (SACC) and pulmonary metastasis may lead to in treatment failure. miR-582-5p plays important roles in tumorigenesis, invasion and migration. Here, we aim to determine the effect of miR-582-5p and its role in SACC invasion and metastasis. METHODS: Six primary human SACC samples and matching adjacent normal tissues were analyzed by microarray analysis. Next, quantitative real-time PCR was carried out to evaluate miR-582-5p expression in 16 primary human SACC samples and matching adjacent normal tissues. Cell invasion and migration were also analyzed, and a luciferase reporter assay and western analysis were conducted. Cell growth and apoptosis assay were performed to confirm the effect of miR-582-5p and Forkhead box C1 (FOXC1) siRNA in cell proliferation and apoptosis. SACC tumorigenesis and metastasis were investigated in vivo experiment. Clinical samples from 110 patients were analyzed using in situ hybridization and immunohistochemistry. RESULTS: Microarray analysis revealed that miR-582-5p was significantly downregulated in the SACC samples compared with the matching adjacent normal tissues. Regulation of miR-582-5p expression significantly influenced the migration, invasion and proliferation ability of SACC cells by targeting FOXC1. E-cadherin was increased, while vimentin and snail were decreased with downregulation of FOXC1, suggesting that FOXC1 may regulate the epithelial-to-mesenchymal transition (EMT) of SACC cells by transactivating snail. In vivo, miR-582-5p overexpression suppressed the tumorigenesis and pulmonary metastasis of SACC. Lower expression of miR-582-5p expression predicts unfavorable prognoses and high rates of metastasis. CONCLUSIONS: miR-582-5p could suppress effect on the process of invasion and migration in SACC cell lines, and this could occur through its target gene FOXC1.

CXCL12-induced upregulation of FOXM1 expression promotes human glioblastoma cell invasion.

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor; it is highly aggressive and is associated with a poor prognosis. Binding of the chemokine CXCL12 to its receptors (CXCR4 and CXCR7) contributes to the activation of many downstream signaling pathways and promotes the invasion of various malignant tumor cells, including GBM cells. FOXM1, a transcription factor involved in cell cycle regulation, is overexpressed in GBM and is involved in GBM progression. However, the molecular mechanisms by which CXCL12 promotes the invasion of human GBM cells remain unclear. In this study, we demonstrate that CXCL12 increases the production of FOXM1 by binding to CXCR4 in GBM cell lines. Furthermore, pretreatment with an inhibitor of the PI3K/AKT pathway abrogated the CXCL12-induced expression of FOXM1. In addition, there was a positive correlation between CXCL12/CXCR4 expression and FOXM1 expression in human malignant glioma tissues. Finally, a functional assay revealed that CXCL12 does not stimulate GBM cell invasion when FOXM1 expression is silenced using a small interfering RNA (siRNA). Collectively, these findings suggest that CXCL12 promotes GBM cell invasion in part by increasing the expression of FOXM1, which is mediated in part by a PI3K/AKT-dependent mechanism in vitro.

Adenovirus-mediated transfection with glucose transporter 3 suppresses PC12 cell apoptosis following ischemic injury.

In this study, we investigated the effects of adenovirus-mediated transfection of PC12 cells with glucose transporter 3 after ischemic injury. The results of flow cytometry and TUNEL showed that exogenous glucose transporter 3 significantly suppressed PC12 cell apoptosis induced by ischemic injury. The results of isotopic scintiscan and western blot assays showed that, the glucose uptake rate was significantly increased and nuclear factor kappaB expression was significantly decreased after adenovirus-mediated transfection of ischemic PC12 cells with glucose transporter 3. These results suggest that adenovirus-mediated transfection of cells with glucose transporter 3 elevates the energy metabolism of PC12 cells with ischemic injury, and inhibits cell apoptosis.

IGF-1 induces hypoxia-inducible factor 1α-mediated GLUT3 expression through PI3K/Akt/mTOR dependent pathways in PC12 cells.

Glucose metabolism is essential for most mammalian neurons, and the passage of glucose across cell membranes is mainly facilitated by glucose transporter 3 (GLUT3). In ischemia/reperfusion injured brains, increase of IGF-1 secretion and GLUT3 up-regulation, are regarded as protective processes. Recent works have shown that various growth factors and cytokines including IGF-1 can stimulate HIF-1α expression, thereby triggering transcription of numerous hypoxia-inducible genes by oxygen-independent mechanisms. So, we hypothesized that HIF-1α might play important role in the process of IGF-1 induced GLUT3. Using echinomycin, a HIF-1 inhibitor, and HIF-1α siRNA, we demonstrated IGF-1 induced GLUT3 expression through HIF-1α in neuronal PC12 cells. Moreover, IGF-1 stimulated HIF-1α and GLUT3 protein expression through phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR dependent pathways. Analysis of GLUT3 promoter deletion sequences indicated that a putative hypoxia-response element (HRE) was critical in GLUT3 promoter activity when PC12 cells were treatment with CoCl(2) and IGF-1. In conclusion, we showed that the expression of GLUT3 in response to IGF-1 was dependent on PI-3-kinase and mTOR activity, and required the transcription factor HIF-1α.

HMME-based PDT restores expression and function of transporter associated with antigen processing 1 (TAP1) and surface presentation of MHC class I antigen in human glioma.

Numerous studies have established that photodynamic therapy (PDT) can trigger tumor-specific immunity and cancer cell immunogenicity, both of which play a critical role in the long-term control of oncogenesis; however, the underlying mechanisms are largely unexplained. Deficiency of the transporter associated with antigen processing 1 (TAP1) has been observed in a variety of tumors, and the question has been raised whether the restoration of TAP1 could facilitate the activation of antitumor immunity. To elucidate the mechanisms underlying PDT-induced immunopotentiation, we examined the hypothesis that upregulating TAP1 via PDT may contribute to enhancement of antitumor immunity and cancer cell immunogenicity. In this study, we investigated the effects of PDT on the expression and function of TAP1 in glioma cells. We found that HMME-based PDT restored TAP1 expression in a rapid and transient manner. Furthermore, the newly synthesized TAP1 protein was capable of potentiating the activity of transporting antigen peptides. As a result, restoration of the expression and function of TAP1 translated into augmenting the presentation of surface MHC class I molecules. Overall, our data indicate that PDT enables glioma cells to recover both the expression of functional TAP1 and the presentation of surface MHC class I antigens, which are processes that may enhance antitumor immunity after PDT. These findings may have implications for PDT and provide new insights into the mechanisms underlying PDT-induced immunopotentiation.