bims-meluca 2020-09-20 papers

Thorac Cancer. 2020 Sep 18.

Expression and role of p16 and GLUT1 in malignant diseases and lung cancer: A review.

Aldo Pezzuto, Michela D'Ascanio, Alberto Ricci, Alessandra Pagliuca, Elisabetta Carico.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death and in most cases it is often diagnosed at an advanced stage. Many genetic and microenvironmental factors are able to modify the cell cycle inducing carcinogenesis and tumor growth. Among the metabolic and genetic factors that come into play in carcinogenesis and tumor cell differentiation and growth there are two different proteins that should be considered which are glucose transporters (GLUTs) and p16INK4 The first are glucose transporters which are strongly involved in tumor metabolism, notably accelerating cancer cell metabolism both in aerobic and anaerobic conditions. There are different subtypes of GLUT family factors of which GLUT 1 is the most important and widely expressed. By contrast, p16 is mainly a tumor-suppressor protein that acts on cyclin-dependent kinase favoring cell cycle arrest in the G1 phase. Our search focused on the action of the aforementioned factors.

Keywords: Glucose transporters; lung cancer; p16 expression

DOI: https://doi.org/10.1111/1759-7714.13651

J Cancer. 2020 ;11(20): 6090-6100

Role of the erythropoietin receptor in Lung Cancer cells: erythropoietin exhibits angiogenic potential.

Xiaoqing Liu, Amanda Tufman, Juergen Behr, Rosemarie Kiefl, Torsten Goldmann, Rudolf M Huber.

Background: Recombinant human erythropoietin (rHuEPO), a hormone regulating the proliferation and differentiation of erythroid cells, is one of the prescription drugs used to treat cancer-associated anemia. However, administration of rHuEPO to cancer patients has been reported to be associated with decreased survival, and the mechanism by which it acts remains controversial. The present study aimed to investigate the expression of the EPO-receptor in lung cancer cell lines and whether rHuEPO treatment affected its growth and migration. Moreover, the angiogenic effects of rHuEPO were also explored in vivo. Methods: Expression of the EPO-receptor in lung cancer cell lines was measured by Western blotting and enzyme linked immunosorbent assays (ELISAs). Proliferation of the lung cancer cells was monitored in the presence of rHuEPO. Human umbilical vein endothelial cells (HUVECs) were used for tube formation assays in vitro, and transwell migration assays were performed to detect migration under rHuEPO treatment. Matrigel plug technology was employed to observe the angiogenic effects in both nude mice and Matrigel-containing lung cancer cell lines H838 or H1975. Microvessel density (MVD) was measured using CD31 Immunohistochemistry (IHC) staining. Results: EPO-receptor (EPO-R) was only detected in the cell lines H838 and H1339 by ELISA. However, the EPO-R protein was detected in all cell lines by Western blotting, which is in contradiction to the ELISA results. Proliferation and migration were not affected by rHuEPO treatment. However, rHuEPO promoted HUVEC tube formation in vitro and significantly induced the formation of new blood vessels in vivo. Furthermore, rHuEPO did not antagonize the inhibitory effects of Afatinib (epidermal growth factor receptor-tyrosine kinase inhibitor; EGFR-TKI) in simultaneous treatment with rHuEPO. In a 3D cell co-culture model, rHuEPO did not enhance the secretion of vascular endothelial growth factor (VEGF) in lung cancer cells or human lung fibroblast cell line MRC-5. Conclusions: We have shown that the role of EPO goes beyond erythropoiesis, also playing a strong role in angiogenesis by participating in new blood vessel formation in lung cancer models. Thus, rHuEPO may raise the risk of thrombosis and metastasis in vivo. Additionally, our results suggest that studies using commercially available EPO-R antibodies should be reexamined; some of these antibodies may not in fact recognize EPO-R.

Keywords: angiogenesis; erythropoietin; erythropoietin receptor; in vivo; lung cancer cells

DOI: https://doi.org/10.7150/jca.36924

Cell Death Dis. 2020 Sep 14. 11(9): 751

MT1DP loaded by folate-modified liposomes sensitizes erastin-induced ferroptosis via regulating miR-365a-3p/NRF2 axis in non-small cell lung cancer cells.

Chengcheng Gai, Chuanliang Liu, Xinghan Wu, Mengyu Yu, Jie Zheng, Weifen Zhang, Shijun Lv, Wentong Li.

Although ferroptosis has been recognized as a novel antitumoral treatment, high expression of nuclear factor erythroid 2-related factor 2 (NRF2) has been reported to be an antioxidant transcript factor that protects malignant cells from ferroptosis. Previous findings indicated that metallothionein 1D pseudogene (MT1DP), a long noncoding RNA (lncRNA), functioned to aggravate oxidative stress by repressing antioxidation. Here we aimed at assessing whether MT1DP could regulate erastin-induced ferroptosis on non-small cell lung cancer (NSCLC) and elucidating the mechanism. We found that ectopic expression of MT1DP sensitized A549 and H1299 cells to erastin-induced ferroptosis through downregulation of NRF2; in addition, ectopic MT1DP upregulated malondialdehyde (MDA) and reactive oxygen species (ROS) levels, increased intracellular ferrous iron concentration, and reduced glutathione (GSH) levels in cancer cells exposed to erastin, whereas downregulation of MT1DP showed the opposite effect. RNA pulldown assay and dual-luciferase reporter assay confirmed that MT1DP modulated the expression of NRF2 via stabilizing miR-365a-3p. As low solubility of erastin limits its efficient application, we further prepared folate (FA)-modified liposome (FA-LP) nanoparticles for targeted co-delivery of erastin and MT1DP to enhance the bioavailability and the efficiency of the drug/gene combination. Erastin/MT1DP@FA-LPs (E/M@FA-LPs) sensitized erastin-induced ferroptosis with decreased cellular GSH levels and elevated lipid ROS. In vivo analysis showed that E/M@FA-LPs had a favorable therapeutic effect on lung cancer xenografts. In short, our findings identify a novel strategy to elevate erastin-induced ferroptosis in NSCLCs acting through the MT1DP/miR-365a-3p/NRF2 axis.

DOI: https://doi.org/10.1038/s41419-020-02939-3

J Cancer Res Ther. 2020 Jul-Sep;16(4):16(4): 855-859

Evaluation of the relationship between serum ghrelin levels and cancer cachexia in patients with locally advanced nonsmall-cell lung cancer treated with chemoradiotherapy.

Pelin Uysal, Cigdem Usul Afsar, Volkan Sozer, Berrin Inanc, Fulya Agaoglu, Zeynep Gural, Nevin Yaman Fazlıoglu, Caglar Cuhadaroglu, Hafize Uzun.

Background: Ghrelin plays a role in mechanisms related to cancer progression - including cell proliferation, invasion and migration, and resistance to apoptosis in the cell lines from several cancers. We investigated the role of ghrelin levels in cancer cachexia-anorexia in patients with locally advanced nonsmall-cell lung cancer (NSCLC) treated with chemoradiotherapy (CRT).
Materials and Methods: This study involved 84 NSCLC patients who had received concomitant CRT. Blood ghrelin levels were compared before and 3 months after CRT. Meanwhile, changes in body weight of the patients were also investigated with changes in ghrelin levels before and after CRT.
Results: Ghrelin levels were significantly decreased in line with changes in patients' weights in patients receiving CRT (P < 0.001). Serum albumin levels and inflammatory-nutritional index were significantly decreased after radiotherapy (RT) (3.01 ± 0.40 g/dL, 0.38 ± 0.20) when compared with its baseline levels (3.40 ± 0.55 g/dL,P < 0.001; 0.86 ± 0.71,P < 0.001, respectively). Serum C-reactive protein levels were significantly increased after CRT (7.49 ± 6.53 mg/L) when compared with its baseline levels (9.54 ± 3.80 mg/L,P = 0.038). After RT, ghrelin levels in patients were positively correlated with body mass index (r = 0.830,P < 0.001) and albumin (r = 0.758,P < 0.001).
Conclusion: Ghrelin may play a role in the pathogenesis of weight loss in NSCLC patients. Ghrelin seems to be implicated in cancer-related weight loss. Ghrelin, cancer, and RT all together have a role in tumor-related anorexia-cachexia in patients with NSCLC. Results of this study need further evaluation as regards to its potential role as an adjuvant diagnostic or prognostic marker.

Keywords: Cancer cachexia; chemoradiotherapy; ghrelin; locally advanced nonsmall cell lung cancer

DOI: https://doi.org/10.4103/jcrt.JCRT_10_19

J Cancer Res Ther. 2020 Jul-Sep;16(4):16(4): 816-821

The prognostic significance of the 18F-fluorodeoxyglucose positron emission tomography/computed tomography in early-stage nonsmall cell lung cancer.

Caglayan Geredeli, Mehmet Artac, Ismail Kocak, Lokman Koral, Abdullah Sakin, Tamer Altinok, Bugra Kaya, Mustafa Karaagac.

Context: The prognostic criteria for early-stage nonsmall cell lung cancer (NSCLC) wait to be explored.
Aim: In this study, our aim was to evaluate the prognostic significance of the positron emission tomography/computed tomography (PET/CT) maximum standardized uptake value (SUVmax) value of the primary tumor in patients with a diagnosis of early-stage NSCLC who received surgical treatment.
Settings and Design: This was a multicenter retrospective design.
Materials and Methods: Patients who had been diagnosed with early-stage NSCLC and who underwent surgery for the condition were included in this study. The preoperative fluorodeoxyglucose (18F-FDG) PET/CT results of the patients were retrospectively accessed from their medical files. The disease-free survival (DFS) rates of patients who had SUVmax values above and below the determined cutoff value were compared.
Statistical Analysis Used: SPSS version 22 and Kaplan-Meier method were used for statistical analysis.
Results: A total of 92 patients were included in the study. The median age of the patients was 60 years (range: 36-79). The determined cutoff SUVmax value of the primary tumor was 13.6. A comparison of the DFS rates of the patients with an SUVmax value above and below 13.6 revealed a significant difference in patients with Stage I (22.9 months vs. 50.3 months; P = 0.02) and Stage II (28 months vs. 40.4 months; P = 0.04), Stage I + II (43.5 months vs. 26.1 months; P = 0,02), and Stage IIIA (14.7 months vs. 13.6 months; P = 0.92) NSCLC.
Conclusions: We found that in early-stage NSCLC patients, the SUVmax value of the primary mass in 18F FDG PET/CT was a prognostic indicator for the DFS rates.

Keywords: 18F-fluorodeoxyglucose positron emission tomography/computed tomography; early-stage nonsmall cell lung cancer; maximum standardized uptake value

DOI: https://doi.org/10.4103/jcrt.JCRT_911_17

Med Sci Monit. 2020 Sep 18. 26 e922703

TNNC1 Reduced Gemcitabine Sensitivity of Nonsmall-Cell Lung Cancer by Increasing Autophagy.

Xian Ye, Guanghui Xie, Zhijian Liu, Jun Tang, Mingyuan Cui, Chenbin Wang, Chi Guo, Jianfeng Tang.

BACKGROUND As we know, chemotherapy resistance is a critical factor leading to recurrence and metastasis of nonsmall-cell lung cancer (NSCLC). To clarify the key target and potential mechanism of resistance to gemcitabine (GEM) in NSCLC, we selected Gene Expression Omnibus Data Set and statistically analyzed a parent cell group and a GEM-resistant cell group. Results showed that the expression of troponin C1, slow skeletal and cardiac type (TNNC1) in GEM-resistant cells was higher than in parent cells, which implies that TNNC1 was associated with GEM resistance in lung cancer cells. MATERIAL AND METHODS TNNC1 expression level was detected by reverse transcription-quantitative polymerase chain reaction or western blot in GEM-resistant patient serum and cell lines. It could reduce or increase autophagy response and GEM resistance accordingly by inhibition of the short interfering ribonucleic acid or by forced overexpression of TNNC1 viruses in A549 cell line and GEM-resistant cell line (A549/GemR) respectively. Blocking autophagy with 3-methyladenine increased the sensitivity of chemotherapy confirmed by flow cytometry and microtubule-associated protein 1A/1B - light chain 3 punctate assay. What's more, in a loss-of-function model, silencing of forkhead box 03 (FOXO3) in A549/GemR cells could rescue the autophagy weakened by TNNC1. RESULTS TNNC1 promoted GEM chemoresistance of NSCLC by activating cytoprotective autophagy, regulated negatively by FOXO3. This research may provide a completely new strategy for NSCLC treatment. CONCLUSIONS Targeting the TNNC1/FOXO3 signaling pathway in NSCLC may be a novel strategy to combat GEM resistance.

DOI: https://doi.org/10.12659/MSM.922703