Y Chromosome LncRNA Are Involved in Radiation Response of Male Non-Small Cell Lung Cancer Cells.

Numerous studies have implicated changes in the Y chromosome in male cancers, yet few have investigated the biological importance of Y chromosome noncoding RNA. Here we identify a group of Y chromosome-expressed long noncoding RNA (lncRNA) that are involved in male non-small cell lung cancer (NSCLC) radiation sensitivity. Radiosensitive male NSCLC cell lines demonstrated a dose-dependent induction of linc-SPRY3-2/3/4 following irradiation, which was not observed in radioresistant male NSCLC cell lines. Cytogenetics revealed the loss of chromosome Y (LOY) in the radioresistant male NSCLC cell lines. Gain- and loss-of-function experiments indicated that linc-SPRY3-2/3/4 transcripts affect cell viability and apoptosis. Computational prediction of RNA binding proteins (RBP) motifs and UV-cross-linking and immunoprecipitation (CLIP) assays identified IGF2BP3, an RBP involved in mRNA stability, as a binding partner for linc-SPRY3-2/3/4 RNA. The presence of linc-SPRY3-2/3/4 reduced the half-life of known IGF2BP3 binding mRNA, such as the antiapoptotic HMGA2 mRNA, as well as the oncogenic c-MYC mRNA. Assessment of Y chromosome in NSCLC tissue microarrays and expression of linc-SPRY3-2/3/4 in NSCLC RNA-seq and microarray data revealed a negative correlation between the loss of the Y chromosome or linc-SPRY3-2/3/4 and overall survival. Thus, linc-SPRY3-2/3/4 expression and LOY could represent an important marker of radiotherapy in NSCLC. SIGNIFICANCE: This study describes previously unknown Y chromosome-expressed lncRNA regulators of radiation response in male NSCLC and show a correlation between loss of chromosome Y and radioresistance. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/19/4046/F1.large.jpg.

Emerging insights of tumor heterogeneity and drug resistance mechanisms in lung cancer targeted therapy.

The biggest hurdle to targeted cancer therapy is the inevitable emergence of drug resistance. Tumor cells employ different mechanisms to resist the targeting agent. Most commonly in EGFR-mutant non-small cell lung cancer, secondary resistance mutations on the target kinase domain emerge to diminish the binding affinity of first- and second-generation inhibitors. Other alternative resistance mechanisms include activating complementary bypass pathways and phenotypic transformation. Sequential monotherapies promise to temporarily address the problem of acquired drug resistance, but evidently are limited by the tumor cells' ability to adapt and evolve new resistance mechanisms to persist in the drug environment. Recent studies have nominated a model of drug resistance and tumor progression under targeted therapy as a result of a small subpopulation of cells being able to endure the drug (minimal residual disease cells) and eventually develop further mutations that allow them to regrow and become the dominant population in the therapy-resistant tumor. This subpopulation of cells appears to have developed through a subclonal event, resulting in driver mutations different from the driver mutation that is tumor-initiating in the most common ancestor. As such, an understanding of intratumoral heterogeneity-the driving force behind minimal residual disease-is vital for the identification of resistance drivers that results from branching evolution. Currently available methods allow for a more comprehensive and holistic analysis of tumor heterogeneity in that issues associated with spatial and temporal heterogeneity can now be properly addressed. This review provides some background regarding intratumoral heterogeneity and how it leads to incomplete molecular response to targeted therapies, and proposes the use of single-cell methods, sequential liquid biopsy, and multiregion sequencing to discover the link between intratumoral heterogeneity and early adaptive drug resistance. In summary, minimal residual disease as a result of intratumoral heterogeneity is the earliest form of acquired drug resistance. Emerging technologies such as liquid biopsy and single-cell methods allow for studying targetable drivers of minimal residual disease and contribute to preemptive combinatorial targeting of both drivers of the tumor and its minimal residual disease cells.

NORAD Expression Is Associated with Adverse Prognosis in Esophageal Squamous Cell Carcinoma.

BACKGROUND: NORAD (non-coding RNA-activated by DNA damage) is a conserved, abundant, and broadly expressed long non-coding RNA, which functions to preserve genome stability. However, its prognostic significance in esophageal squamous cell carcinoma (ESCC) remains unclear. MATERIAL AND METHODS: The expression of NORAD was detected by quantitative real-time polymerase chain reaction in pairs of tumorous and adjacent normal tissues derived from 106 ESCC patients. We analyzed the potential relationship between NORAD expression levels in tumor tissues and clinicopathological features of ESCC patients and clinical outcome. RESULTS: The relative expression levels of NORAD were significantly upregulated in tumor tissues (p < 0.001) compared to adjacent normal tissues. In addition, high expression of NORAD was correlated with larger tumor size (p = 0.021) and T stage (p = 0.045). Kaplan-Meier analysis indicated that patients with high NORAD expression had poor overall and disease-free survival (p < 0.001). Moreover, multivariate analysis showed that increased expression of NORAD was an independent predictor of overall survival (p = 0.001). CONCLUSION: Our data indicate that increased NORAD expression might serve as a novel molecular predictor of poor prognosis in ESCC patients and maybe a potential target for diagnosis and gene therapy.

AXL-GAS6 expression can predict for adverse prognosis in non-small cell lung cancer with brain metastases.

PURPOSE: Patients with non-small cell lung cancer (NSCLC) brain metastases (BM) have poor clinical outcomes. We sought to determine if AXL-GAS6 expression can be used as independent prognostic biomarkers for NSCLC BM. METHODS: We retrospectively studied the medical records of 98 patients diagnosed with advanced metastatic NSCLC from December 2000 to June 2014. Out of a total of 98 patients with NSCLC metastases, 66 patients were identified to have brain metastases. The expressions of AXL and GAS6 were assessed by standard immunohistochemistry and correlated with clinicopathological factors and overall survival (OS) outcomes. RESULTS: The expression of AXL was positively associated with GAS6 expression (P < 0.001), and tumor differentiation (P = 0.014) in advanced NSCLC with metastases. AXL expression displayed no association with gender, age, smoking history, pathology, T stage, N stage, CEA, and LDH. In univariate analysis, both AXL and GAS6 were found to predict worse OS outcomes (AXL: HR 1.77, 95% CI 1.13-2.79, P = 0.01; GAS6: HR 1.80, 95% CI 1.14-2.84, P = 0.01). In the brain metastasis subgroup, the expression of AXL was positively associated with GAS6 expression (P < 0.001). Both AXL and GAS6 were found to predict worse BM-OS outcomes in univariate analysis (AXL: HR 2.19, 95% CI 1.33-4.10, P = 0.005; GAS6: HR 2.04, 95% CI 1.01-3.71, P = 0.019). In multivariate analysis, high co-expression of AXL/GAS6 was found to be an independent unfavorable risk factor for the overall study population (HR 2.33, 95% CI 1.40-3.87, P = 0.0011) and also in BM (HR 2.76, 95% CI 1.45-5.25, P = 0.001), predicting worse survival outcome. CONCLUSIONS: AXL-GAS6 co-expression represents a potential independent prognostic biomarker for survival outcome in NSCLC BM patients.