Background: KH-type splicing regulatory protein (KHSRP) plays an important role in cancer invasion, but the relevant mechanism is not well known. In the present study, we investigated the function and potential molecular mechanism of KHSRP in non-small cell lung cancer (NSCLC) metastasis and elucidated its clinical significance. Methods: Isobaric tags for relative and absolute quantitation and the SWATH™ approach were combined with nanoliquid chromatography-tandem mass spectrometry analysis to identify metastasis-associated nucleoproteins in NSCLC. Real-time PCR and Western blot were used to screen for metastasis-associated candidate molecules. Gene knockdown and overexpression were used to investigate their functions and molecular mechanisms in lung cancer cells. Coimmunoprecipitation (Co-IP) experiments were performed to identify the interactions between candidate molecules and their interacting proteins. Gene expression and its association with multiple clinicopathologic characteristics were analyzed by immunohistochemistry (IHC) and Western blot in human lung cancer specimens. Results: KHSRP was identified as a metastasis-associated candidate molecule. In NSCLC cell lines, knockdown of KHSRP significantly reduced lung cancer cell proliferation, migration, and invasion in vitro and in vivo, whereas overexpression of KHSRP did the opposite. Mechanistically, the protein heterogeneous nuclear ribonucleoprotein C (C1/C2) (HNRNPC) was identified to interact with KHSRP using Co-IP experiments. In NSCLC cell lines, overexpression of HNRNPC significantly promoted lung cancer cell proliferation, migration, and invasion in vitro and in vivo. KHSRP and HNRNPC may induce human lung cancer cell invasion and metastasis by activating the IFN-α-JAK-STAT1 signaling pathway. Drastically higher expression levels of KHSRP and HNRNPC were observed in lung cancer tissues compared to those in adjacent noncancerous tissues. Increased KHSRP and HNRNPC expression was significantly associated with advanced tumor stages and metastasis (both lymph node and distant). Kaplan-Meier survival analysis showed that patients with high KHSRP and HNRNPC expression levels were predicted to have the shortest survival times and to have a poor prognosis. Conclusions: KHSRP plays an important role in NSCLC metastasis and may serve as a potential prognostic marker and novel therapeutic target for lung cancer metastasis treatment.

It is urgent to identify new biomarkers and therapeutic targets to ameliorate the clinical prognosis of patients with lung cancer. The functional significance and molecular mechanism of dynein cytoplasmic 1 heavy chain 1 (DYNC1H1) in nonsmall cell lung cancer (NSCLC) progression is still elusive. In our current study, publicly available data and Western blotting experiments confirmed that DYNC1H1 expression was upregulated in lung cancer samples compared with noncancerous samples. Quantitative real-time PCR (qPCR) results indicated that high DYNC1H1 expression in lung cancer tissues was significantly associated with clinical tumor stage and distal metastasis; moreover, its high expression was negatively correlated with prognosis. Functional experiments demonstrated that DYNC1H1 loss of function caused a significant decrease in cell viability and cell proliferative ability, inhibition of the cell cycle, and promotion of both migration potential and invasion potential in vitro. Animal experiments by tail vein injection of lung cancer cells showed that DYNC1H1 knockdown significantly decreased lung cancer metastasis. Mechanistically, the results from a human protein array showed changes in the IFN-γ-JAK-STAT signaling pathway, and analysis of The Cancer Genome Atlas (TCGA) immune data demonstrated that disturbance of the immune microenvironment might be involved in the impaired growth and metastatic ability mediated by DYNC1H1 loss in NSCLC. DYNC1H1 might serve as a promising biological marker of prognosis and a potential clinical therapeutic target for patients with NSCLC.

Approximately 90% of patients diagnosed with non-small cell lung cancer (NSCLC) die due to distant metastases. However, the complicated molecular and cellular mechanisms involved in lung cancer metastasis remain poorly understood. Copine III (CPNE3), a member of a Ca²⁺-dependent phospholipid-binding protein family, was identified as a novel metastasis-associated protein in NSCLC in our previous study, however, its function in metastasis remains unclear. Here, we found that CPNE3 was expressed at high levels in NSCLC tissues and advanced TNM stages and was significantly associated with poor prognosis. In addition, CPNE3 interacted with phosphorylated erb-b2 receptor tyrosine kinase 2 (pErbB2) and receptor of activated protein C kinase 1 (RACK1) and activated the focal adhesion (FA) signaling pathway in NSCLC cells. Moreover, knockdown of RACK1 inhibited cell motility in the CPNE3-overexpressed NSCLC cells. These findings offer mechanistic insights into the oncogenic roles of CPNE3 and the pivotal effects of CPNE3 as a biomarker and therapeutic target for NSCLC metastasis.

Background: Long noncoding RNAs (lncRNAs) play a key role in the development and progression of many cancer types, including lung cancer. The objective of this study is to examine the function and molecular mechanism of lncRNAs involved in non-small cell lung cancer (NSCLC). Methods: First, 7 lung cancer-related differentially expressed LncRNAs were screened from 2 genomic profiling datasets. Of these lncRNAs, FOXF1 adjacent noncoding developmental regulatory RNA (FENDRR) was found to be the only one that was both significantly down-regulated in the patients with advanced pathology and negatively correlated with prognosis. Thus, lncRNA FENDRR was further studied in this project. Clinical correlation analysis was further conducted in the GSE30219 dataset and 73 paired lung cancer and noncancerous tissues stored in our lab; Subsequently, we evaluated FENDRR coding potential with the Phylogenetic Codon Substitution Frequencies (PhyloCSF), Coding-Potential Assessment Tool (CPAT), and Coding Potential Calculator (CPC) online analytical tool. The cell growth ability was measured by CCK8 assay and clonogenicity assay, the metastatic capacities were evaluated using Transwell migration and invasion assays. Mechanistically, we analyzed the correlation of FENDRR function in NSCLC with immune response by utilizing The Cancer Genome Atlas (TCGA) data. Results: Results indicated a negative clinical correlation of FENDRR. Coding potential analysis showed FENDRR as a noncoding RNA. Elevated expression of FENDRR led to cell growth arrest, inhibition of proliferative ability, declined migration and invasion potential of NSCLC cells in vitro. Mechanistically, we discovered that FENDRR expression might be involved in aberrant immune response regulation. Conclusions: Taken together, our results provide a greater understanding of lncRNA FENDRR as a tumor suppressor with respect to tumor-immune interactions in NSCLC.

The existence of cancer stem cells (CSCs), marked by CD133, is the primary cause of death in hepatocellular carcinoma (HCC). Here, we generated a new risk model comprising the signatures of four genes highly correlated with CD133 (CD133((hi))) that help improve survival in HCC. Three datasets were used to identify the differential CD133((hi)) genes by comparing sorted CD133+ liver CSCs and CD133-differentiated counterparts. Univariate analysis was used to screen significantly differential CD133((hi)) genes associated with overall survival in the training dataset, which were used for risk model construction. High-risk patients were strongly associated with poor survival by Kaplan-Meier survival analysis in both the training and validation datasets. Clinical stratification analyses further demonstrated that the risk factors acted as independent factors and that high-risk patients were characterized by more aggressive cancer features. Functional enrichment analyses performed by gene set enrichment analysis (GSEA) and the Database for Annotation, Visualization and Integrated Discovery (DAVID) revealed that high-risk patients showed the disturbance of immune hepatic homeostasis involving aberrant immune cells, including macrophages and T and B cells, and an abnormal inflammatory response including the IL6/Jak/STAT3 pathway and TNF signaling pathway. In conclusion, our constructed CD133((hi)) gene risk model provides a resource for understanding the role of CD133(+) CSCs in the progression of HCC in terms of tumor-immune interactions.

Objective: Bone metastasis from patients with advanced lung adenocarcinoma (LAC) is a very serious complication. To better understand the molecular mechanism, our current study sheds light on identification of hub genes mediating bone metastatic spread by combining bioinformatic analysis with functional verification.