Zongwu Lin

USP7 overexpression predicts a poor prognosis in lung squamous cell carcinoma and large cell carcinoma

In non-small cell lung cancer (NSCLC), both USP7 expression and p53 gene status were reported to be an indicator of poor prognosis in adenocarcinoma patients; however, its roles and mechanisms in lung squamous cell carcinoma and large cell carcinoma need to be clarified. The USP7 expression was examined in NSCLC tumors (excluding adenocarcinoma), their corresponding non-tumorous tissues, and NSCLC cells. Then, the prognostic role of USP7 was analyzed in 110 NSCLC samples (excluding the adenocarcinoma). Finally, the roles and mechanisms of USP7 in the proliferation, metastasis, and invasion of a NSCLC cell were assessed using a specific vshRNA. The USP7 expression was higher in NSCLC tissues compared to non-tumorous samples, accordingly, the high level of USP7 was detected in NSCLC cell lines compared with HBE cell. After the USP7 downregulation, the H460 cells exhibited decreased metastasis/invasion in vitro and in vivo. The preliminary mechanism study indicated overexpression of USP7 might regulate the p53-MDM2 pathway by inducing the MDM2 de-ubiquitination and subsequent stabilization, which resulted in the upregulation of the Bad phosphorylation. Additionally, we also found that USP7 might induce cell epithelial-mesenchymal transition to enhance the cell invasive ability. Clinically, USP7 overexpression significantly correlated with malignant phenotype. Furthermore, the 5-year overall survival in patients with USP7low was higher than that of USP7high. Multivariate analysis showed USP7 overexpression was an independent prognostic marker for these cancers. USP7 overexpression may regulate the survival and invasive properties of squamous cell carcinoma and large cell carcinoma cells, and may serve as a molecular target.

The overexpression of 14‐3‐3ζ and Hsp27 promotes non–small cell lung cancer progression

The 14‐3‐3ζ protein has been identified as a putative oncoprotein in several cancers, including non–small cell lung cancer (NSCLC). However, the mechanisms underlying its functions have not been well defined.

Identification of immunohistochemical markers for distinguishing lung adenocarcinoma from squamous cell carcinoma

BACKGROUND Immunohistochemical staining has been widely used in distinguishing lung adenocarcinoma (LUAD) from lung squamous cell carcinoma (LUSC), which is of vital importance for the diagnosis and treatment of lung cancer. Due to the lack of a comprehensive analysis of different lung cancer subtypes, there may still be undiscovered markers with higher diagnostic accuracy. METHODS Herein first, we systematically analyzed high-throughput data obtained from The Cancer Genome Atlas (TCGA) database. Combining differently expressed gene screening and receiver operating characteristic (ROC) curve analysis, we attempted to identify the genes which might be suitable as immunohistochemical markers in distinguishing LUAD from LUSC. Then we detected the expression of six of these genes (MLPH, TMC5, SFTA3, DSG3, DSC3 and CALML3) in lung cancer sections using immunohistochemical staining. RESULTS A number of genes were identified as candidate immunohistochemical markers with high sensitivity and specificity in distinguishing LUAD from LUSC. Then the staining results confirmed the potentials of the six genes (MLPH, TMC5, SFTA3, DSG3, DSC3 and CALML3) in distinguishing LUAD from LUSC, and their sensitivity and specificity were not less than many commonly used markers. CONCLUSIONS The results revealed that the six genes (MLPH, TMC5, SFTA3, DSG3, DSC3 and CALML3) might be suitable markers in distinguishing LUAD from LUSC, and also validated the feasibility of our methods for identification of candidate markers from high-throughput data.

Regulation of CXCR4/AKT-signaling-induced cell invasion and tumor metastasis by RhoA, Rac-1, and Cdc42 in human esophageal cancer

CXC chemokines and their cognate receptors have been implicated wildly in cancer pathogenesis. In the present study, we report a critical cause relationship between CXCR4 expression and tumorigenesis in the setting of human esophageal squamous cell carcinoma (ESCC). In ESCC cells, CXCR4 expression was significantly higher than in human esophageal epithelial cells (HEEC). Reduction of CXCR4 in ESCC cells reduced cell proliferation and invasion in vitro and tumor growth in vivo. Among the potential downstream targets of CXCR4-CXCL12 are RhoA, Rac-1, and Cdc42, which are likely to contribute to the invasiveness of ESCC cells. Finally, we found that CXCR4-CXCL12/AKT axis regulates RhoA, Rac-1, and Cdc42 to modulate cell invasion and tumor metastasis. Together, these results demonstrate a role for CXCR4 in ESCC metastasis and progression and suggest potential targets for therapeutic intervention.

Landscape of expression profiles in esophageal carcinoma by The Cancer Genome Atlas data.

In this study, we explored the gene and microRNA (miRNA) expressions profile of esophageal carcinoma. The expression data for messenger RNAs and miRNAs in normal and cancerous esophageal tissues were obtained from the Cancer Genome Atlas database and then the differentially expressed genes and miRNAs were identified. As a result, we identified 2962 genes and 45 miRNAs differentially expressed in esophageal carcinoma compared with normal esophageal tissues. Subsequently, the altered gene functions and signaling pathways were investigated using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, and these differentially expressed genes were significantly enriched in the cell cycle, cell migration, mitogen-activated protein kinase (MAPK) and toll-like receptor signaling pathway, and so on. Then the regulatory relationships between the differentially expressed miRNAs and genes were examined with Targetscan and Miranda, and the potential target sites of transcription factors (TFs) in the promoter regions of these miRNAs and genes were identified using the TRANSFAC database. Finally the TF-miRNA-gene network in esophageal cancer was established, summarizing the regulatory links among the TFs, differentially expressed miRNAs and differentially expressed genes. Factors such as core promoter-binding protein (CPBP), nuclear factor of activated T-cells 1 (NFAT-1), miR-30c-5p, were located in the central hub of this network, highlighting their vital roles in esophageal tumorigenesis. These findings may extend our understanding of the molecular mechanisms underlying esophageal carcinoma and promote new perspectives for prevention, diagnosis and treatment.

Capn4 promotes non-small cell lung cancer progression via upregulation of matrix metalloproteinase 2

The expression of calpain small subunit 1 (Capn4) is correlated with the invasion of several types of tumors. However, the roles of Capn4 in non-small cell lung cancer (NSCLC) remain unclear. In this study, we found that the expression of Capn4 in NSCLC tissues was much higher than that in nontumorous samples. High levels of Capn4 expression were associated with lymph node metastasis and large tumor size in NSCLC patients. The 5-year overall survival rate in the Capn4high group was significantly lower than that in the Capn4low group. In multivariate analysis, Capn4 was identified as an independent prognostic factor for overall survival. Moreover, in an in vitro analysis, downregulation of Capn4 expression by siRNA suppressed the invasive potential of lung cancer cells. Finally, we demonstrated that Capn4 enhanced the invasion ability of lung cancer cells by upregulating the expression of matrix metalloproteinase 2. Our findings indicated that Capn4 may represent a potential therapeutic target and a novel prognostic marker of NSCLC.

Lymph node metastasis in clinical stage IA peripheral lung cancer

OBJECTIVES To investigate lymph node metastasis especially the intrapulmonary node in clinical IA peripheral lung cancer patients to evaluate the indications for lung segmentectomy in lymph node level. MATERIALS AND METHODS Patients (n=292) with clinical stage IA peripheral lung cancer received radical lobectomy at our department between October 2013 and July 2014 were enrolled in our study. Lymph nodes were obtained during routine surgical procedures while segmental lymph nodes were dissected from the resected lobe for pathological examination. New classification for pulmonary adenocarcinoma with each histologic component was also analyzed. RESULTS The percentage of patients found to have no lymph node metastasis was 90.4% (264/292). Tumor size on computed tomography and tumor consistency were independent predictors for lymph node metastasis. Tumor with a dominant ground-glass opacity (GGO) component was a good predictor for lymph node metastasis (p<0.001). Metastasis was more common in larger tumors (p<0.001), but there was non-tumor bearing segment metastasis even in tumor less than 1cm. Patients with micropapillary or solid component were correlated with lymph node metastasis (p=0.001 and p=0.009, respectively). CONCLUSIONS The rate of metastasis to the lymph nodes is very low in clinical stage IA peripheral lung cancer patients. Patients with a dominant GGO component on CT might be the suitable candidates for lung segmentectomy because of almost no lymph node metastasis. Careful selection should be made for the patients with tumor size ≤2 cm who had metastasized nodes in non-tumor bearing segment when considering segmentectomy. If the resected tumor had micropapillary or solid component, the lobectomy might be considered.

Prognostic value of visceral pleural invasion in non-small cell lung cancer: A propensity score matching study based on the SEER registry

Visceral pleural invasion (VPI) is considered a poor prognostic factor in non‐small cell lung cancer (NSCLC). We aimed to analyze the effect of VPI on cancer‐specific survival, using propensity score matching (PSM) based on the Surveillance, Epidemiology, and End Results database.

Mutations and expression of the NFE2L2/KEAP1/CUL3 pathway in Chinese patients with lung squamous cell carcinoma

BACKGROUND Recent studies have reported an abnormally high alteration rate in the nuclear factor erythroid 2-like 2 (NFE2L2)/kelch-like ECH-associated protein 1 (KEAP1)/cullin 3 (CUL3) pathway. But the status of this pathway in Chinese patients with lung squamous cell carcinoma (SqCC) has not been thoroughly studied, and there are many uncertainties regarding the expression of pathway intermediates. METHODS cDNA sequencing and TaqMan qRT-PCR were carried out in paired cancer and adjacent normal samples obtained from 100 Chinese patients with lung SqCC. Immunohistochemical staining was performed in 50 other paraffin-embedded specimens. RESULTS We detected 47 mutations in 36 patients (36%), and 143 single nucleotide polymorphism (SNP) in 59 patients (59%), of which 41 mutations and 31 SNPs resulted in amino acid (AA) and possibly functional changes. By combining qRT-PCR and immunohistochemistry staining, we confirmed that the expression of NFE2L2 and KEAP1 were highly increased, while the expression of CUL3 was not significantly changed in lung SqCC samples from Chinese patients. CONCLUSIONS Considering the frequent mutations and abnormal expression, the NFE2L2/KEAP1/CUL3 pathway may play an important role in the therapy of Chinese patients with lung SqCC.

Uniportal video-assisted thoracoscopic surgery right upper lobectomy with systematic lymphadenectomy in a semiprone position

A 53-year-old male smoker was referred to our hospital with an enlarged lesion in the right upper lung. Computed tomography (CT) showed a 1.5 cm solid lesion with pleural indentation in the right upper lobe adjacent to the oblique fissure. The preoperative clinical diagnosis was stage I primary lung cancer. Uniportal video-assisted thoracoscopic surgery (VATS) right upper lobectomy in a semiprone position was performed in this case. Frozen section examination confirmed the diagnosis of lung adenocarcinoma, and systematic lymphadenectomy was then performed. A chest tube was placed at the posterior part of the incision through the dorsal thoracic cavity to the apex. The postoperative pathologic diagnosis was T2aN0M0 adenocarcinoma.