Neurotransmitters: Impressive regulators of tumor progression.

In contemporary times, tumors have emerged as the primary cause of mortality in the global population. Ongoing research has shed light on the significance of neurotransmitters in the regulation of tumors. It has been established that neurotransmitters play a pivotal role in tumor cell angiogenesis by triggering the transformation of stromal cells into tumor cells, modulating receptors on tumor stem cells, and even inducing immunosuppression. These actions ultimately foster the proliferation and metastasis of tumor cells. Several major neurotransmitters have been found to exert modulatory effects on tumor cells, including the ability to restrict emergency hematopoiesis and bind to receptors on the postsynaptic membrane, thereby inhibiting malignant progression. The abnormal secretion of neurotransmitters is closely associated with tumor progression, suggesting that focusing on neurotransmitters may yield unexpected breakthroughs in tumor therapy. This article presents an analysis and outlook on the potential of targeting neurotransmitters in tumor therapy.

MiRNA signature predicts the response of patients with advanced lung adenocarcinoma to platinum-based treatment.

BACKGROUND: Accumulating literature proved that miRNAs can regulate the sensitivity of platinum and act as a promising candidate to predict the response of patients with lung adenocarcinoma to chemotherapy. However, most studies on miRNAs were restricted to in vitro experiments. This study aimed to evaluate whether miRNAs alone or in combination (miRNA signature) can act as predictive biomarkers of platinum-based chemotherapy in patients with lung adenocarcinoma. METHODS: Eight miRNAs that most probably predict the efficacy of platinum were screened in 111 tumor tissues of lung adenocarcinoma. Univariate and multivariate Cox analyses, Kaplan-Meier survival curve analysis, Chi-square test, and univariate and multivariate logistic regression analyses were employed to determine whether miRNA expression is associated with the response of patients to platinum-based chemotherapy. The maximum significant odds ratio value was acquired by multiple cycles of multivariate logistic regression analysis. The cut-off points of miRNAs were obtained. A miRNA chemo-sensibility index (CI) formula was established, and its prediction performance was confirmed in another independent set (n = 31). RESULTS: Underexpression of three miRNAs (miRNA-21, miRNA-125b, and miRNA-224) was independently associated with the chemotherapy sensitivity of patients with lung adenocarcinoma. The miRNA CI formula containing these three miRNAs was calculated as (1.364 × miR-21) + (1.323 × miR-125b) + (1.131 × miR-224). A high CI was related to platinum-based chemotherapy resistance, and its prediction performance was confirmed in the testing set. The MAPK, PI3K-Akt, Ras, and cGMP-PKG signaling pathways were considered to be most probably correlated with platinum resistance. CONCLUSION: Our miRNA CI formula can act as an independent predictor to predict the response of patients with lung adenocarcinoma to platinum-based chemotherapy.

Epithelial-to-mesenchymal transition correlates with gefitinib resistance in NSCLC cells and the liver X receptor ligand GW3965 reverses gefitinib resistance through inhibition of vimentin.

The role of epithelial-to-mesenchymal transition in cancer drug resistance is increasingly acknowledged. We examined whether epithelial-to-mesenchymal transition affects gefitinib resistance in non-small cell lung cancer (NSCLC) cells. Cell viability was detected by CCK-8 assay, VIM expression levels were determined by quantitative real-time polymerase chain reaction. Western blot and immunocytochemistry were performed to determine the protein expression level of vimentin. We observed morphologic differences between gefitinib-sensitive and -insensitive cells. Compared with the sensitive parental cell line, HCC827, vimentin expression levels were increased in HCC827 cells with acquired gefitinib resistance. Vimentin expression was also markedly upregulated in cells with intrinsic gefitinib resistance, and upregulated vimentin expression was correlated with gefitinib sensitivity. Our previous study demonstrated that coadministration of gefitinib and GW3965 resulted in decreased cell proliferation and induced apoptosis. Therefore, we investigated the relationship among GW3965, vimentin, and gefitinib resistance in NSCLC cells by analysis of the expression of vimentin in cells treated with a combination of gefitinib and GW3965. Gefitinib treatment led to increased levels of intracellular vimentin, while combined treatment with gefitinib and GW3965 resulted in decreased vimentin expression levels through reduction of gefitinib drug resistance in NSCLC cells. Overall, these findings suggest that vimentin expression is associated with sensitivity to gefitinib, and our study highlights the potential usefulness of the drug, GW3965, for reversal of gefitinib resistance through inhibition of vimentin expression.

Genome-wide profiling of micro-RNA expression in gefitinib-resistant human lung adenocarcinoma using microarray for the identification of miR-149-5p modulation.

To understand the mechanism involved in gefitinib resistance, we established gefitinib-resistant human HCC827/GR-8-1 cell line from the parental HCC827 cell line. We compared the micro-RNA expression profiles of the HCC827 cells HCC827/GR-8-1 using Agilent micro-RNA microarrays. The micro-RNAs, such as the miR-149-5p, were up- or downregulated and associated with acquired gefitinib resistance. Quantitative real-time polymerase chain reaction was then performed to verify the expression patterns of different micro-RNAs. The result showed that miR-149-5p was upregulated in the HCC827/GR-8-1 cell line. To investigate the biological function of miR-149-5p in non-small cell lung cancer cells acquired gefitinib resistance, we examined cell proliferation using a cell counting kit-8 assay. Cell viability was evaluated after the miR-149-5p mimics, inhibitors, and negative control were separately transfected into the non-small cell lung cancer cells. The results showed that the non-small cell lung cancer cells transfected with miR-149-5p mimics exhibited reduced cell motility. The drug-sensitivity assay results revealed that the overexpression of miR-149-5p effectively evaluates the half maximal inhibitory concentration values of the cell in response to gefitinib, and the downregulation of miR-149-5p can attenuate the half maximal inhibitory concentration values of the cell lines in response to gefitinib. Furthermore, the levels of miR-149-5p in the HCC827 and HCC827/GR-8-1 cells were inversely correlated with caspase-3 expression. In conclusion, this study revealed that miR-149-5p is upregulated in the HCC827/GR-8-1 cells and involved in the acquired gefitinib resistance.

Elevated serum levels of vascular endothelial growth factor predict a poor prognosis of platinum-based chemotherapy in non-small cell lung cancer.

AIM: This study was designed to investigate the predictive and prognostic values of serum vascular endothelial growth factor (VEGF) level in non-small cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy. METHODS: Patients' peripheral blood samples were collected prior to chemotherapy and after 1 week of the third cycle of combination chemotherapy. Serum VEGF levels were evaluated through Luminex multiplex technique. Between September 2011 and August 2015, a total of 135 consecutive advanced or recurrent histologically verified NSCLC patients were enrolled in the study. Moreover, all the patients received platinum-based combination chemotherapy as a first-line treatment. RESULTS: No significant associations were found between pretreatment serum VEGF levels and clinical characteristics, such as sex (P=0.0975), age (P=0.2522), stage (P=0.1407), lymph node metastasis (P=0.6409), tumor location (P=0.3520), differentiated degree (P=0.5608), pathological (histological) type (P=0.4885), and response to treatment (P=0.9859). The VEGF load per platelet (VEGFPLT) levels were not correlated with sex, age, primary tumor site, and pathological type in NSCLC patients (all P>0.05). The median survival time of progression-free survival (PFS) was 6.407 and 5.29 months in the low and high groups, respectively, when using 280 pg/mL VEGF level as the cutoff point (P=0.024). CONCLUSION: In conclusion, the serum VEGF levels were found to be a poor prognostic biomarker for the efficacy of platinum-based chemotherapy in terms of PFS, but it was not shown to be a suitable predictive marker for clinical response to platinum-based chemotherapy.

Liver X receptors agonist GW3965 re-sensitizes gefitinib-resistant human non-small cell lung cancer cell to gefitinib treatment by inhibiting NF-κB in vitro.

The recent research shows that the inhibition of the nuclear factor-κB (NF-κB) pathway is a promising therapeutic option for patients who progress after treatment with the novel mutant-selective EGFR-TKIs. For propose to find a nontoxic drug to reverse the acquired gefitinib resistance, we examined whether the Liver X Receptors agonist GW3965 affect gefitinib resistance of HCC827/GR-8-2 cells. Cell viability was measured by CCK-8 assay. Levels of NF-κB, p-AKT and caspases were detected by Western blot analysis. Immunocytochemical analysis was used to detect the expression of NF-κB, p-AKT intracellularly. Induction of apoptosis and cell cycle arrest was measured by Flow cytometry assay. And results revealed that more than 90% of HCC827/GR-8-2 cells lived upon treatment with gefitinib at a dose of 5µM for 48h. However, when under the combine treatment of GW3965 (5µM) & gefitinib(5µM), cell death rate was increased observably. Co-administration of gefitinib & GW3965 induced cell apoptosis and cell cycle arrest. Additionally, we observed a dose-dependent- down-regulation of NF-κB in HCC827/GR-8-2 cells treated with gefitinib & GW3965. GW3965 and gefitinib synergistically decreased cell proliferation and induced apoptosis by inhibiting NF-κB signaling pathway in gefitinib resistant cells. These findings support our hypothesis that GW3965 could act as a useful drug to reverse the gefitinib resistance.

[Relationship of clusterin expression with Bax and p53 expression in non-small cell lung cancer].

BACKGROUND: It has been proven that clusterin is a newly apoptosis-related factor and upregulates in many tumors. It plays important roles in carcinogenesis and tumor progression. The antiapoptosis of clusterin seems to be relative to other antiapoptosis factors. The aim of this study is to investigate the expression and significance of clusterin in non-small cell lung cancer (NSCLC) tissue. METHODS: The expression of clusterin, p53 and Bax in NSCLC were detected by immunohistochemical SP method and Western blot assay. RESULTS: Positive expression rate of clusterin was 79.25% (42/53) in NSCLC tissues which was much higher than that in normal lung tissue (2/16, 12.50%) (Chi-square=23.68, P < 0.05). The expression of clusterin was closely related to pathological differentiation (rs=0.464, P < 0.01), clinical stage (rs =0.320, P < 0.01) and lymph node metastasis (rs=0.255, P < 0.05), but not correlated to the sex (Chi-square=0.007, P > 0.05), age (Chi-square=0.707, P > 0.05) and histological type (Chi-square=0.702, P > 0.05). The expression of clusterin in NSCLC was positively correlated to the expression of p53 (rs=0.589, P < 0.01), but was negatively related to the expression of Bax (rs =-0.346, P < 0.01). The relative expression level of clusterin protein in NSCLC was significantly higher than that in normal lung tissue (0.541±0.010 vs 0.201±0.020) (P < 0.05). CONCLUSIONS: Clusterin may play an important role in the biological characteristics of NSCLC by the antiapoptosis pathway.

[Analysis of genes related to sensitivity to navalbine and docetaxel in 10 lung cancer cell lines].

OBJECTIVE: To analyze the drug-sensitivity-related genes to anti-tumor drugs navalbine (NVB) and docetaxel (Doc) in four SCLC and six NSCLC cell lines. METHODS: The sensitivity of 4 SCLC lines and 6 NSCLC lines to NVB and to Doc was determined with MTT test. The expression of 1291 anti-tumor drug sensitivity-related genes in the 10 cell lines was assayed by cDNA macroarray technique, and cluster analysis was performed to find the relationship between the results obtained by the above mentioned two measurements. RESULTS: (1) The anti-tumor effect of NVB on the 10 cell lines was apparently better than that of Doc. (2) The drug sensitivity-related genes in these 10 cell lines showed a more close positive correlation with Doc than that with NVB, whereas more genes showed negative correlation with NVB than that with Doc. But in 6 NSCLC cell lines, more genes showed the same positive or negative correlation with the two drugs. (3) 51 genes in the 10 cell lines showed correlation with Doc or NVB. 13 of them had negative correlation with Doc, 11 of them showed positive correlation. 24 of them showed negative correlation with NVB, 3 of them showed positive correlation. 67 genes in 6 NSCLC cell lines showed a correlation with sensitivity to Doc or NVB, among them 34 had negative correlation with Doc, 4 had positive correlation. 25 genes had negative correlation with NVB, 4 had positive correlation. (4) Rab 1, Rab 3, Rho B, Rho C, Rac 1, Rac 2, Gho GDI beta, CD44, integrin alpha5, integrin alpha6, integrin beta5, vinculin showed to be cytoskeleton-related genes differently expressing in SCLC or NSCLC cell lines. CONCLUSION: There is obvious difference in the drug sensitivity-related genes to NVB or Doc between SCLC and NSCLC cell lines.