BackgroundThe highly refractory nature of non-small cell lung cancer (NSCLC) to chemotherapeutic drugs is an important factor resulting in its poor prognosis. Recent studies have revealed that tumour necrosis factor alpha-induced protein 8 (TNFAIP8) is involved in various biological and pathological processes of cells, but their underlying mechanisms in processes ranging from cancer development to drug resistance have not been fully elucidated.MethodsTNFAIP8 expression in clinical NSCLC samples was examined through immunohistochemistry (IHC). After adjusting for patients’ characteristics with propensity score matching, Kaplan-Meier analysis and Cox regression analysis were performed for comparison of patients’ survival according to the TNFAIP8 level. Lentiviral transfection with TNFAIP8-specific shRNAs was used to establish stable TNFAIP8 knockdown (TNFAIP8 KD) NCI-H460, A549 and cis-diamminedichloroplatinum II resistant A549 (A549/cDDP) cell lines. Cell proliferation and viability were assessed by CCK-8 assay. Cell cycle was examined by flow cytometry. Multiple pathways regulated by TNFAIP8 KD were revealed by microarray analysis.ResultsWe found that high TNFAIP8 expression was associated with advanced pT stage, advanced pTNM stage, lymph node metastasis and unfavourable survival in NSCLC patients. TNFAIP8 shRNAs reduced in vitro cancer cell proliferation and in vivo tumor growth. Additionally, TNFAIP8 KD increased the sensitivity of NSCLC cells to cisplatin in vitro and in vivo. Conversely, up-regulation of TNFAIP8 promoted the proliferation and drug resistance to cisplatin of NSCLC cells. TNFAIP8 influences cancer progression pathways involving the MDM2/p53 pathway. Indeed, we observed that TNFAIP8 KD mediated the MDM2 downregulation and the p53 ubiquitination, thereby decreasing the degradation of p53 protein. shRNA p53 reversed TNFAIP8 shRNA-mediated regulation of cell proliferation, cell cycle, cisplatin sensitivity, and expression levels of RAD51, a DNA repair gene.ConclusionOur work uncovers a hitherto unappreciated role of TNFAIP8 in NSCLC proliferation and cisplatin chemoresistance that is mediated through the MDM2/p53 pathway. These findings might offer potential therapeutic targets for reversing cisplatin resistance in NSCLC patients with high TNFAIP8 expression.Electronic supplementary materialThe online version of this article (10.1186/s12964-018-0254-x) contains supplementary material, which is available to authorized users.

BackgroundLRH1, which promotes the malignant transformation of carcinoma, has recently been documented in several types of malignancies. However, LRH1 has not been assessed as a potential clinical biomarker in any cancer.MethodsLRH1 expression was tested in fresh‐frozen tissue samples with quantitative real‐time PCR and Western blot analysis. Surgically resected tumor tissues were collected from 156 non‐small cell lung cancer (NSCLC) patients: 75 with adenocarcinoma and 81 with squamous cell carcinoma. Subsequently, the immunohistochemical expression of LRH1 was examined, and its clinical significance was evaluated.ResultsLRH1 overexpression was observed in NSCLC carcinoma tissues compared to adjacent normal lung tissues. LRH1 expression was correlated with poorer differentiation (P = 0.023), pathological tumor classification (P < 0.001), advanced pathological tumor node metastasis stage (P = 0.017), adenocarcinoma subtype (P = 0.031), and positive lymph node metastasis (P < 0.001). Multivariate analysis demonstrated that LRH1 expression status was an independent prognostic factor for overall (hazard ratio 1.372, 95% confidence interval 1.225–1.617; P = 0.003) and disease‐free survival (hazard ratio 1.497, 95% confidence interval 1.059–2.115; P = 0.011) in patients who suffered from resectable NSCLC.ConclusionThe results of our study indicate that LRH1 predicts NSCLC progression, metastasis, and a dismal prognosis, emphasizing its promising role as a novel target in NSCLC therapies.

Background PH domain and leucine‐rich repeat protein phosphatase 2 (PHLPP2) has been reported to be a potent tumor suppressor in many human cancers. However, PHLPP2 has not been fully researched as a putative clinical prognostic biomarker of lung cancer. Methods The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases including data on 1383 non‐small cell lung cancer (NSCLC) patients were used to determine PHLPP2 expression. PHLPP2 expression was then examined by immunohistochemistry, and its clinical significance analyzed in 134 NSCLC patients, including 73 patients with adenocarcinoma and 81 with squamous cell carcinoma. Results We found PHLPP2 expression to be less pronounced in NSCLC tissue samples than that in nontumoral lung tissues according to data taken from TCGA and GEO datasets; this outcome was further validated by immunohistochemistry assay. The low PHLPP2 expression level was found to be associated with the presence of lymph node metastasis (P = 0.003). Importantly, PHLPP2 was found to be an independent indicator of prognosis for overall (hazard ratio [HR] = 0.520, 95% confidence interval [Cl] = 0.327–0.827; P = 0.006) and disease‐free survival (HR = 0.489, 95% Cl = 0.308–0.775; P = 0.002) in patients with surgically‐resected NSCLC by multivariate analysis. Conclusion Taken together, our findings show that PHLPP2 is a robust clinical marker for NSCLC survival and could serve as a potential therapeutic target.