Inhibitor of Differentiation-1 as a Novel Prognostic Factor in NSCLC Patients with Adenocarcinoma Histology and Its Potential Contribution to Therapy Resistance

Abstract

Purpose: High inhibitor of differentiation-1 (Id1) levels have been found in some tumor types. We aimed to study Id1 levels and their prognostic impact in a large series of stages I to IV non-small cell lung cancer (NSCLC) patients. Experiments in cell lines and cells derived from malignant pleural effusions (MPE) were also carried out.Experimental Design: A total of 346 NSCLC samples (three different cohorts), including 65 matched nonmalignant tissues, were evaluated for Id1 expression by using immunohistochemistry. Additional data from a fourth cohort including 111 patients were obtained for Id1 mRNA expression analysis by using publicly available microarrays. In vitro proliferation assays were conducted to characterize the impact of Id1 on growth and treatment sensitivity.Results: Significantly higher Id1 protein levels were found in tumors compared with normal tissues (P < 0.001) and in squamous carcinomas compared with adenocarcinomas (P < 0.001). In radically treated stages I to III patients and stage IV patients treated with chemotherapy, higher Id1 levels were associated with a shorter disease-free survival and overall survival in adenocarcinoma patients in a log-rank test. A Cox model confirmed the independent prognostic value of Id1 levels for both stages I to III and stage IV patients. In silico analysis confirmed a correlation between higher Id1 mRNA levels and poor prognosis for adenocarcinoma subjects. In vitro Id1 silencing in radio/chemotherapy-resistant adenocarcinoma cells from MPEs restored sensitivity to both therapies.Conclusions: In our series, Id1 levels showed an independent prognostic value in patients with adenocarcinoma, regardless of the stage. Id1 silencing may sensitize adenocarcinoma cells to radiotherapy and chemotherapy. Clin Cancer Res; 17(12); 4155-66. Ó2011 AACR.

Id-1, Id-2, and Id-3 co-expression correlates with prognosis in stage I and II lung adenocarcinoma patients treated with surgery and adjuvant chemotherapy

“…In agreement with Ponz-Sarvis et al, 37 our analyses showed a significantly higher expression of Id-1 protein in ADC tissue compared with normal lung tissue. Unexpectedly, Bhattacharya et al 33 showed significantly lower Id-1 mRNA expression levels in ADC and matched normal but no IHC staining was performed to confirm the 34 conducted an investigation in malignant cell lines from small cell lung cancer and found that Id-1 gene was up-regulated.…”

“…As we observed that the majority of tumor cells expressed nuclear Ids, we applied a modified H-score, where the extension of nuclear intensity of staining was scored as percentage of positive cells and the intensity of staining was assessed compared with a known external positive control. Actually, there has been uncertainty about staining for Ids and its relationship with different histological type 33,34,37,38 ) and how best to record staining for Ids. Yang et al 42 employed a semi-quantitative score in breast carcinoma classified by plus into four groups: þ, 0-10%; þþ, 10-20%; þþþ, 20-30%; þþþþ, 30-40%.…”

The Antitumor Activity of Plant-Derived Non-Psychoactive Cannabinoids

“…Drugs that stimulate ROS have been shown to sensitize tumors to first-line agents (Wondrak, 2009). Moreover, using genetic approaches to down-regulate Id1 expression has re-sensitized aggressive cancer cells to treatments with first-line therapies (Hu et al, 2009; Ponz-Sarvise et al, 2011). In breast cancer cells, where CBD is effective at downregulating Id1 expression, CBD enhanced the activity of the first-line agent, paclitaxel (Ward et al, 2014).…”

Suppression of lung metastases by the CD26/DPP4 inhibitor Vildagliptin in mice

“…Reducing SDS-PAGE was performed and samples were blotted onto a PVDF-membrane. p62 (MBL), CDC2, pCDC2, PTEN, Cleaved caspase3, LC3, ATF4, AKT, pAKT (Cell signaling), E-cadherin, N-cadherin, Vimentin (Abcam) and ID1 [24] antibodies were tested. Loading control was a rabbit anti-GAPDH (Abcam) and anti-beta actin (Sigma-Aldrich).…”