Association of miR-141 and miR-200c with time to recurrence (TTR) and overall survival (OS) in resected non-small-cell lung cancer (NSCLC) adenocarcinoma (ADC) patients (p).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7547-7547
Author(s):  
Marc Campayo ◽  
Alfons Navarro ◽  
Rut Tejero ◽  
Maria L Cabanas ◽  
Laureano Molins ◽  
...  
Keyword(s):  
Surgical Resection ◽  
Prognostic Value ◽  
Epithelial Mesenchymal Transition ◽  
Early Stage ◽  
Stage I ◽  
Mesenchymal Transition ◽  
Early Stage Nsclc ◽  
Time To Recurrence ◽  
Resected Nsclc

7547 Background: Surgical resection remains the standard curative treatment for early-stage NSCLC, but nearly 50% of p experience recurrence, highlighting the need for novel diagnostic and therapeutic strategies. Moreover, treatments in NSCLC are often histology-dependent, underlining the need for histology-related markers. MicroRNAs (miRNAs) are promising molecular markers in cancer, with marked differences in expression according to histology. miR-200 family members have been associated in vitro with the regulation of epithelial-mesenchymal transition. We have examined their impact on outcome in resected NSCLC p. Methods: We analyzed miRNA expression using TaqMan assays in 160 tumor samples from NSCLC p who had undergone surgical resection and correlated our findings with TTR and OS. Results: p characteristics: age, 67 (51-83); 140 male; 96 (60%) stage I, 34 (21.3%) stage II, 30 (18.7%) stage III; 77(48.1%) ADC, 71(44.4%) squamous cell carcinoma (SCC); 16 (9.1%) received adjuvant treatment. With a median follow-up of 28 months (m), 64 p (40%) had relapsed. TTR for the 107 p with high miR-200c was 26.7 m vs 100.2 m for the 52 p with low miR-200c (P=0.032). OS for p with high miR-200c was 71.2 m vs. 125 m for p with low miR-200c (P=0.01). TTR for 112 p with high miR-141 was 26.7 m vs. 100.2 m for 46 p with low miR-141 (P=0.06). OS for p with high miR-141 was 72 m vs. 118 m for p with low miR-141 (P=0.02). Interestingly, neither miR-200c nor miR-141 correlated with TTR or OS in SCC p. In contrast, in ADC p, the prognostic value of both miRNAs increased: miR-200c (TTR, P=0.01; OS, P<0.0001) and miR-141 (TTR, P=0.003; OS, P<0.0001). This prognostic value was maintained in the subgroup of stage I p: miR-200c (TTR, P=0.011; OS, P<0.001) and miR-141 (TTR, P=0.018; OS, P<0.001). In the multivariate analysis, miR-200c and miR-141 emerged as an independent prognostic factor for OS (OR: 3.2, P=0.006; OR:2.5, P=0.02, respectively) together with age>65 (OR: 3.3, P=0.001) and stage I (OR: 0.3, P=0.004). Conclusions: miR-200c and miR-141 expression is associated with TTR and OS in resected ADC but not in SCC NSCLC p.

Neoadjuvant pembrolizumab (Pembro) for early stage non-small cell lung cancer (NSCLC): Updated report of a phase I study, MK3475-223.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 8534-8534 ◽  
Author(s):  
Jair Bar ◽  
Damien Urban ◽  
Efrat Ofek ◽  
Aliza Ackerstein ◽  
Ilanit Redinsky ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Early Stage ◽  
Clinical Stage ◽  
Predictive Biomarkers ◽  
Dose Schedule ◽  
Stage I ◽  
Early Stage Nsclc ◽  
Resected Nsclc ◽  
Prolonged Air Leak

8534 Background: Resected NSCLC clinical stage I or II harbor a 5 year survival of only 30-50%. Immunotherapy might be more effective in low-burden disease. We hypothesized that neo-adjuvant immunotherapy is a feasible, safe and effective treatment (Tx) for early stage NSCLC. Methods: MK3475-223 is an ongoing phase I study of neoadjuvant pembrolizumab in stage I-II NSCLC. All Pembro Txs are 200mg q 3 weeks (wks). Objectives: determine safety; recommended phase 2 dose/schedule; pathological & radiological response. Doses-schedule limiting toxicities (DLT) were defined as significant surgical complications (bleeding, delayed wound healing, ARDS, prolonged air-leak) or a significant delay of surgery. The doses-schedule escalation cohorts were (i) single pembro dose 3 wk prior to surgery; (ii) 2 pembro doses, 2 wks later surgery; (iii) 2 pembro doses, 1 wk later surgery. Expansion cohort received the doses-schedule of cohort (iii). Percentages of remaining viable tumor in the post-Tx were assessed, 10% or less was considered amajor pathological response (MPR). IHC for pre-Tx PDL1 was done. Efficacy was evaluated for the patients who had received 2 doses of pembrolizumab. Results: No DLT occurred in the dose-schedule escalation cohorts. 10 patients received 2 cycles of neo-adjuvant pembrolizumab. 4 patients achieved a MPR (4/10 who received 2 cycles of pembro; 40%; 95% C.I. 16.7-68.8%). No correlation is seen between the levels of PDL1 pre-Tx and the pathologic response. Size of the tumor and N status was also not in any apparent correlation with MPR (data not shown). Interestingly, all of the MPR cases had a relatively long interval from 1st Tx till surgery. Clinical trial information: NCT02938624. Conclusions: Neo-adjuvant pembro is safe and feasible. A promising sign of efficacy is seen. Achieving MPR might require a longer 1st-Tx-surgery interval. Predictive biomarkers for response might be different from those in advanced disease. Recruitment and correlative studies are ongoing.[Table: see text]

Increased BRCA1 mRNA: An independent prognostic variable in completely resected chemo-naive non-small cell lung cancer (NSCLC) patients (p)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7551-7551
Author(s):  
R. Rosell ◽  
E. Jassem ◽  
M. Skrzypski ◽  
M. Taron ◽  
P. Mendez ◽  
...  
Keyword(s):  
Adjuvant Chemotherapy ◽  
Epithelial Mesenchymal Transition ◽  
Excision Repair ◽  
Cox Model ◽  
Distant Metastases ◽  
Genetic Alterations ◽  
Stage I ◽  
Mesenchymal Transition ◽  
Real Time Quantitative Pcr ◽  
Resected Nsclc

7551 Background: Following surgical resection in operable NSCLC, 5-year survival is 60% in stage I, 39% in stage IIB and 23% in stage IIIA, with relapse commonly as distant metastases. The average benefit of adjuvant chemotherapy is 5%, ranging from nil in stage I to 15% in stage II-IIIA. Caretaker genes involved in keeping genetic alterations to a minimum include the nucleotide excision repair genes ERCC1 and myeloid zinc finger 1 (MZF1), which mediates ERCC1 expression, and other stability genes, such as BRCA1, which control processes involving large portions of chromosomes. Thioredoxin-1 (TRX1) is a redox protein overexpressed in NSCLC that is correlated with poor prognosis, and TWIST contributes to metastasis by promoting epithelial-mesenchymal transition. Methods: In order to identify p with a high risk of relapse, we investigated the expression of these 5 transcripts in frozen resected tumors from 126 resected NSCLC p by real-time quantitative PCR. Gene expression was normalized using β-actin and 18SrRNA expression as internal references. Results: Adenocarcinoma (adeno), 33 p; squamous cell carcinoma (SCC), 93 p. Stage: IA, 18 p; IB, 53 p; IIB, 33 p; IIIA, 22 p. Tumoral transcript expression with β-actin: ERCC1, 1.23; MZF1, 0.53; BRCA1, 3.65; TRX1, 1.82; TWIST, 7.75. A strong correlation was observed between the expression of ERCC1, MZF1 and BRCA1 (P<0.001). Expression of each of the 5 transcripts was higher in SCC than in adeno (P<0.001). Median survival (MS): low ERCC1 (<1.5) = not reached (NR), high ERCC1 = 33 months (m) (P=0.21); low MZF1 (<0.5) = NR, high MZF1 = 33 m (P=0.04); low BRCA1 (<5) = NR, high BRCA1 = 22 months (m) (P=0.01); low TRX1 (<0.8) = NR, high TRX1 = 39.5 m (P=0.02); no differences in MS according to levels of TWIST. In a multivariate Cox model for survival, BRCA1 and stage emerged as independent prognostic variables ( Table ). Conclusion: Increased BRCA1 is associated with shorter survival, and BRCA1 assessment could be useful for customizing adjuvant chemotherapy. No significant financial relationships to disclose. [Table: see text]

scholarly journals Toll-like receptor 3 as a new marker to detect high risk early stage Non-Small-Cell Lung Cancer patients

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Francesca Bianchi ◽  
Massimo Milione ◽  
Patrizia Casalini ◽  
Giovanni Centonze ◽  
Valentino M. Le Noci ◽  
...  
Keyword(s):  
High Risk ◽  
Tumor Cells ◽  
Immune Cells ◽  
Prognostic Value ◽  
Early Stage ◽  
Prognostic Significance ◽  
Stage I ◽  
Poor Overall Survival ◽  
Early Stage Nsclc ◽  
Tlr3 Expression

Abstract Immune and epithelial cells express TLR3, a receptor deputed to respond to microbial signals activating the immune response. The prognostic value of TLR3 in cancer is debated and no data are currently available in NSCLC, for which therapeutic approaches that target the immune system are providing encouraging results. Dissecting the lung immune microenvironment could provide new prognostic markers, especially for early stage NSCLC for which surgery is the only treatment option. In this study we investigated the expression and the prognostic value of TLR3 on both tumor and immune compartments of stage I NSCLCs. In a cohort of 194 NSCLC stage I, TLR3 immunohistochemistry expression on tumor cells predicted a favorable outcome of early stage NSCLC, whereas on the immune cells infiltrating the tumor stroma, TLR3 expression associated with a poor overall survival. Patients with TLR3-positive immune infiltrating cells, but not tumor cells showed a worse prognosis compared with all other patients. The majority of TLR3-expressing immune cells resulted to be macrophages and TLR3 expression associates with PD-1 expression. TLR3 has an opposite prognostic significance when expressed on tumor or immune cells in early stage NCSCL. Analysis of TLR3 in tumor and immune cells can help in identifying high risk stage I patients for which adjuvant treatment would be beneficial.

scholarly journals Silencing of UBE2D1 Inhibited Cell Migration in Gastric Cancer, Decreasing Ubiquitination of SMAD4

2021 ◽  
Author(s):  
Honghu Xie ◽  
Yu He ◽  
Yugang Wu ◽  
Qicheng Lu
Keyword(s):  
Gastric Cancer ◽  
Cell Migration ◽  
Mouse Model ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Early Stage ◽  
Transforming Growth Factor Β ◽  
Mesenchymal Transition

Abstract Background: Gastric cancer (GC) is the second leading cause of cancer-related deaths. Because it is hard to diagnose at early stage, the overall 5 years survival rate is lower than 25%. High migration is the main hallmark of malignant cells at advanced stage of GC. Thus, it is urgent to find biomarkers for early diagnosis and more effective therapy of GC.Methods: In this study, silencing and overexpression lentiviruses targeting the ubiquitin-conjugating enzyme E2 D1 (UBE2D1), transwell, wound healing, and pulmonary metastasis mouse model were applied to analyze the function of UBE2D1 in vitro and in vivo. Real-time PCR and immunohistochemistry were used to elucidate the level of UBE2D1 in GC samples.Results: Silencing of UBE2D1 inhibited cell migration and the levels of Epithelial-mesenchymal transition (EMT) makers (MMP2 and MMP9) in AGS and MKN45 cells. Silencing of UBE2D1 inhibited cell metastasis in mouse model. On the contrary, UBE2D1 overexpression increased cell migration and the levels of MMP2 and MMP9 in MGC-803 cells. Further, silencing of UBE2D1 decreased the ubiquitination level of mothers against decapentaplegic homolog 4 (SMAD4), and the increase of cell migration induced by UBE2D1 overexpression could be reversed by SMAD4.Conclusion: Silencing of UBE2D1 inhibited cell migration through transforming growth factor β (TGF-β)/SMAD4 signaling pathway in GC.

scholarly journals Programmed Death–Ligand 1 and Vimentin: A Tandem Marker as Prognostic Factor in NSCLC

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1411 ◽  
Author(s):  
Julien Ancel ◽  
Philippe Birembaut ◽  
Maxime Dewolf ◽  
Anne Durlach ◽  
Béatrice Nawrocki-Raby ◽  
...  
Keyword(s):  
Overall Survival ◽  
Epithelial Mesenchymal Transition ◽  
Early Stage ◽  
Disease Free Survival ◽  
Poor Overall Survival ◽  
Vimentin Expression ◽  
Programmed Death Ligand 1 ◽  
Mesenchymal Transition ◽  
Resected Nsclc ◽  
Programmed Death

In non-metastatic non-small-cell lung cancer (NSCLC), outcomes remain poor. Adjuvant chemotherapies provide a limited improvement in disease-free survival. Recent exploratory studies on early-stage NSCLC show that immunotherapy given according to Programmed Death–Ligand 1 expression generates variable results, emphasizing a need to improve tumor characterization. We aimed to conjointly assess NSCLC, the expression of PD–L1, and epithelial–mesenchymal transition, frequently involved in tumor aggressiveness. 188 resected NSCLCs were analyzed. Among 188 patients with curatively resected NSCLC, 127 adenocarcinomas and 61 squamous cell carcinomas were stained for PD–L1 and vimentin expression. Overall survival has been compared regarding PD–L1 and vimentin statuses both separately and conjointly in Tumor Cancer Genome Atlas databases. PD–L1 and vimentin higher expressions were strongly associated (OR = 4.682, p < 0.0001). This co-expression occurred preferentially in tumors with lymph node invasion (p = 0.033). PD–L1 was significantly associated with high EMT features. NSCLC harboring both PD–L1high/vimentinhigh expressions were significantly associated with poor overall survival (p = 0.019). A higher co-expression of vimentin and PD–L1 was able to identify patients with worse outcomes. Similar to an important prognostic marker in NSCLC, this tandem marker needs to be further presented to anti-PD–L1 immunotherapies to improve outcome.

scholarly journals FXR Acts as a Metastasis Suppressor in Intrahepatic Cholangiocarcinoma by Inhibiting IL-6-Induced Epithelial-Mesenchymal Transition

2018 ◽  
Vol 48 (1) ◽  
pp. 158-172 ◽  
Author(s):  
Bei Lv ◽  
Lijie Ma ◽  
Wenqing Tang ◽  
Peixin Huang ◽  
Biwei Yang ◽  
...  
Keyword(s):  
Cell Lines ◽  
Intrahepatic Cholangiocarcinoma ◽  
Poor Prognosis ◽  
Prognostic Value ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Cholangiocarcinoma Cell

Background/Aims: Intrahepatic cholangiocarcinoma (ICC) is a complicated condition, with difficult diagnosis and poor prognosis. The expression and clinical significance of the farnesoid X receptor (FXR), an endogenous receptor of bile acids, in ICC is not well understood. Methods: Western blotting and immunochemical analyses were used to determine the levels of FXR in 4 cholangiocarcinoma cell lines, a human intrahepatic biliary epithelial cell line (HIBEpic) and 322 ICC specimens, respectively, while quantitative reverse transcription polymerase chain reaction was used to detect the mRNA levels of FXR in cholangiocarcinoma cell lines. We evaluated the prognostic value of FXR expression and its association with clinical parameters. We determined the biological significance of FXR in ICC cell lines by agonist-mediated activation and lentivirus-mediated silence. IL-6 expression was tested by an enzyme-linked immunosorbent assay and flow cytometry. In vitro, cell proliferation was examined by Cell Counting Kit-8, migration and invasion were examined by wound healing and transwell assays; in vivo, tumor migration and invasion were explored in NOD-SCID mice. Results: FXR was downregulated in ICC cell lines and clinical ICC specimens. Loss of FXR was markedly correlated with aggressive tumor phenotypes and poor prognosis in patients with ICC. Moreover, FXR expression also had significant prognostic value in carbohydrate antigen 19-9 (CA19-9) negative patients. The expression of FXR was negatively correlated with IL-6 levels in clinical ICC tissues. FXR inhibited the proliferation, migration, invasion and epithelial mesenchymal transition (EMT) of ICC cells via suppression of IL-6 in vitro. Obeticholic acid, an agonist of FXR, inhibited IL-6 production, tumor growth and lung metastasis of ICC in vivo. Conclusions: FXR could be a promising ICC prognostic biomarker, especially in CA19-9 negative patients with ICC. FXR inhibits the tumor growth and metastasis of ICC via IL-6 suppression.

scholarly journals Silencing of UBE2D1 inhibited cell migration in gastric cancer, decreasing ubiquitination of SMAD4

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Honghu Xie ◽  
Yu He ◽  
Yugang Wu ◽  
Qicheng Lu
Keyword(s):  
Gastric Cancer ◽  
Cell Migration ◽  
Mouse Model ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Early Stage ◽  
Transforming Growth Factor Β ◽  
Mesenchymal Transition

Abstract Background Gastric cancer (GC) is the second leading cause of cancer-related deaths. Because it is hard to diagnose at early stage, the overall 5 years survival rate is lower than 25%. High migration is the main hallmark of malignant cells at advanced stage of GC. Thus, it is urgent to find biomarkers for early diagnosis and more effective therapy of GC. Methods In this study, lentivirus-mediated silencing and overexpression lentiviruses targeting the ubiquitin-conjugating enzyme E2 D1 (UBE2D1), transwell, wound healing, and pulmonary metastasis mouse model were applied to analyze the function of UBE2D1 in vitro and in vivo. Real-time PCR and immunohistochemistry were used to elucidate the level of UBE2D1 in GC samples. Results Silencing of UBE2D1 inhibited cell migration and the levels of epithelial-mesenchymal transition makers (MMP2 and MMP9) in AGS and MKN45 cells. Silencing of UBE2D1 inhibited cell metastasis in mouse model. On the contrary, UBE2D1 overexpression increased cell migration and the levels of MMP2 and MMP9 in MGC-803 cells. Further, silencing of UBE2D1 decreased the ubiquitination level of mothers against decapentaplegic homolog 4 (SMAD4), and the increase of cell migration induced by UBE2D1 overexpression could be reversed by SMAD4. Conclusion Silencing of UBE2D1 inhibited cell migration through transforming growth factor β (TGF-β)/SMAD4 signaling pathway in GC.

scholarly journals MicroRNA-144 Suppresses Prostate Cancer Growth and Metastasis by Targeting EZH2

2021 ◽  
Vol 20 ◽  
pp. 153303382198981
Author(s):  
Xin-bo Sun ◽  
Yong-wei Chen ◽  
Qi-sheng Yao ◽  
Xu-hua Chen ◽  
Min He ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Viability ◽  
Cell Apoptosis ◽  
Epithelial Mesenchymal Transition ◽  
Luciferase Reporter ◽  
Mesenchymal Transition ◽  
Proliferation And Apoptosis ◽  
High Incidence ◽  
Inhibit Cell Proliferation

Background: Prostate cancer is a common malignant tumor with a high incidence. MicroRNAs (miRNAs) have been shown to be important post-transcriptional regulators during tumorigenesis. This study aimed to explore the effect of miR-144 on PCa proliferation and apoptosis. Material and Methods: The expression of miR-144 and EZH2 were examined in clinical PCa tissues. PCa cell line LNCAP and DU-145 was employed and transfected with miR-144 mimics or inhibitors. The correlation between miR-144 and EZH2 was verified by luciferase reporter assay. Cell viability, apoptosis and migratory capacity were detected by CCK-8, flow cytometry assay and wound healing assay. The protein level of EZH2, E-Cadherin, N-Cadherin and vimentin were analyzed by western blotting. Results: miR-144 was found to be negatively correlated to the expression of EZH2 in PCa tissues. Further studies identified EZH2 as a direct target of miR-144. Moreover, overexpression of miR-144 downregulated expression of EZH2, reduced cell viability and promoted cell apoptosis, while knockdown of miR-144 led to an inverse result. miR-144 also suppressed epithelial-mesenchymal transition level of PCa cells. Conclusion: Our study indicated that miR-144 negatively regulate the expression of EZH2 in clinical specimens and in vitro. miR-144 can inhibit cell proliferation and induce cell apoptosis in PCa cells. Therefore, miR-144 has the potential to be used as a biomarker for predicting the progression of PCa.

scholarly journals Overexpressed P75CUX1 promotes EMT in glioma infiltration by activating β-catenin

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Anqi Xu ◽  
Xizhao Wang ◽  
Jie Luo ◽  
Mingfeng Zhou ◽  
Renhui Yi ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Tumor Grade ◽  
Prognostic Indicator ◽  
Migration And Invasion ◽  
Poor Overall Survival ◽  
Mesenchymal Transition ◽  
Kaplan Meier ◽  
Homeobox Protein

AbstractThe homeobox protein cut-like 1 (CUX1) comprises three isoforms and has been shown to be involved in the development of various types of malignancies. However, the expression and role of the CUX1 isoforms in glioma remain unclear. Herein, we first identified that P75CUX1 isoform exhibited consistent expression among three isoforms in glioma with specifically designed antibodies to identify all CUX1 isoforms. Moreover, a significantly higher expression of P75CUX1 was found in glioma compared with non-tumor brain (NB) tissues, analyzed with western blot and immunohistochemistry, and the expression level of P75CUX1 was positively associated with tumor grade. In addition, Kaplan–Meier survival analysis indicated that P75CUX1 could serve as an independent prognostic indicator to identify glioma patients with poor overall survival. Furthermore, CUX1 knockdown suppressed migration and invasion of glioma cells both in vitro and in vivo. Mechanistically, this study found that P75CUX1 regulated epithelial–mesenchymal transition (EMT) process mediated via β-catenin, and CUX1/β-catenin/EMT is a novel signaling cascade mediating the infiltration of glioma. Besides, CUX1 was verified to promote the progression of glioma via multiple other signaling pathways, such as Hippo and PI3K/AKT. In conclusion, we suggested that P75CUX1 could serve as a potential prognostic indicator as well as a novel treatment target in malignant glioma.

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