Jiagen Li

LncRNA profile study reveals a three-lncRNA signature associated with the survival of patients with oesophageal squamous cell carcinoma

Background Oesophageal cancer is one of the most deadly forms of cancer worldwide. Long non-coding RNAs (lncRNAs) are often found to have important regulatory roles. Objective To assess the lncRNA expression profile of oesophageal squamous cell carcinoma (OSCC) and identify prognosis-related lncRNAs. Method LncRNA expression profiles were studied by microarray in paired tumour and normal tissues from 119 patients with OSCC and validated by qRT-PCR. The 119 patients were divided randomly into training (n=60) and test (n=59) groups. A prognostic signature was developed from the training group using a random Forest supervised classification algorithm and a nearest shrunken centroid algorithm, then validated in a test group and further, in an independent cohort (n=60). The independence of the signature in survival prediction was evaluated by multivariable Cox regression analysis. Results LncRNAs showed significantly altered expression in OSCC tissues. From the training group, we identified a three-lncRNA signature (including the lncRNAs ENST00000435885.1, XLOC_013014 and ENST00000547963.1) which classified the patients into two groups with significantly different overall survival (median survival 19.2u2005months vs >60u2005months, p<0.0001). The signature was applied to the test group (median survival 21.5u2005months vs >60u2005months, p=0.0030) and independent cohort (median survival 25.8u2005months vs >48u2005months, p=0.0187) and showed similar prognostic values in both. Multivariable Cox regression analysis showed that the signature was an independent prognostic factor for patients with OSCC. Stratified analysis suggested that the signature was prognostic within clinical stages. Conclusions Our results suggest that the three-lncRNA signature is a new biomarker for the prognosis of patients with OSCC, enabling more accurate prediction of survival.

Isocitrate Dehydrogenase 1 Is a Novel Plasma Biomarker for the Diagnosis of Non–Small Cell Lung Cancer

Purpose: Effective biomarkers for the diagnosis of non–small cell lung cancer (NSCLC) are needed. We previously showed that isocitrate dehydrogenase 1 (IDH1) is significantly increased in NSCLC tumors. This study aimed to examine the plasma levels of IDH1 in a large patient population to evaluate its effectiveness in NSCLC diagnosis. Experimental Design: The plasma levels of IDH1, CA125, Cyfra21-1, and CEA were assayed by ELISA. Blood samples were obtained from 1,422 participants (943 patients with NSCLC and 479 healthy controls). The samples were randomly divided into a training set and a test set. Receiver operating characteristic and binary logistic regression analyses were applied to evaluate diagnostic efficacy and establish diagnostic mathematical models. Results: Plasma IDH1 levels were significantly higher in patients with NSCLCs than in healthy controls (P < 0.001). The diagnostic use of IDH1 in lung adenocarcinoma [area under curve (AUC): 0.858 and 0.810; sensitivity: 77.1% and 76.2%; specificity: 82.9% and 76.6%; in the training set and test set, respectively] was significantly greater than that of CA125, Cyfra21-1, or CEA (P < 0.001). The model combining IDH1 with CEA, CA125, and Cyfra21-1 was more effective for lung adenocarcinoma diagnosis than IDH1 alone (sensitivity and specificity in the training set: 75.8%, 89.6%; test set: 86.3%, 70.7%). In addition, the plasma levels of IDH1 could contribute to the diagnostic model of lung squamous cell carcinoma. Conclusions: IDH1 can be used as a plasma biomarker for the diagnosis of NSCLCs, particularly lung adenocarcinoma, with relatively high sensitivity and specificity. Clin Cancer Res; 19(18); 5136–45. ©2013 AACR.

Xerophilusin B Induces Cell Cycle Arrest and Apoptosis in Esophageal Squamous Cell Carcinoma Cells and Does Not Cause Toxicity in Nude Mice

Esophageal cancer is the eighth most common cancer in the world and ranks as the sixth leading cause of cancer-related mortality. Esophageal cancer has a poor prognosis partially due to its low sensitivity to chemotherapy agents, and the development of new therapeutic agents is urgently needed. Here, the antitumor activity of a natural ent-kaurane diterpenoid, xerophilusin B (1), which was isolated from Isodon xerophilus, a perennial herb frequently used in Chinese folk medicine for tumor treatment, was investigated. Compound 1 exhibited antiproliferative effects against esophageal squamous cell carcinoma (ESCC) cell lines in a time- and dose-dependent manner with lower toxicity against normal human and murine cell lines. In vivo studies demonstrated that 1 inhibited tumor growth of a human esophageal tumor xenograft in BALB/c nude mice without significant secondary adverse effects, indicating its safety in treating ESCC. Furthermore, 1 induced G2/M cell cycle arrest and promoted apoptosis through mitochondrial cytochrome c-dependent activation of the caspase-9 and caspase-3 cascade pathway in ESCC cell lines. In conclusion, the observations herein reported showed that 1 is a potential chemotherapeutic agent for ESCC and merits further preclinical and clinical investigation for cancer drug development.

AJUBA promotes the migration and invasion of esophageal squamous cell carcinoma cells through upregulation of MMP10 and MMP13 expression

The LIM-domain protein AJUBA has been reported to be involved in cell-cell adhesion, proliferation, migration and cell fate decision by acting as a scaffold or adaptor protein. We previously identified AJUBA as a putative cancer gene in esophageal squamous cell carcinoma (ESCC). However, the function and underlying mechanisms of AJUBA in ESCC remain largely unknown. In the present study, we detected AJUBA levels in ESCC tumor tissues and in corresponding adjacent non-tumor tissues by immunohistochemistry (IHC) and investigated the function and mechanism of AJUBA in ESCC cells. The IHC results showed that AJUBA levels were significantly higher in ESCC tissues compared with corresponding adjacent non-tumor tissues (P < 0.001). Both in vitro and in vivo experiments showed that AJUBA promoted cell growth and colony formation, inhibited cisplatin-induced apoptosis of ESCC cells, and promoted ESCC cell migration and invasion. RNA sequencing was used to reveal the oncogenic pathways of AJUBA that were involved, and MMP10 and MMP13 were identified as two of the downstream targets of AJUBA. Thus, AJUBA upregulates the levels of MMP10 and MMP13 by activating ERK1/2. Taken together, these findings revealed that AJUBA serves as oncogenic gene in ESCC and may serve as a new target for ESCC therapy.

Combination of serum miRNAs with Cyfra21-1 for the diagnosis of non-small cell lung cancer

In this study, we screened 381 miRNAs by RT-qPCR in serum samples of 44 NSCLC patients and 22 healthy individuals to identify altered miRNAs, and validated the results in a training and test cohorts with 300 serum samples (178 NSCLC and 122 healthy individuals). Three miRNAs (miR-194, miR-652 and miR-660) were selected from 380 miRNAs by two normalization methods in the discovery cohort, and miR-652 and miR-660 were confirmed to be significantly upregulated in ADC and SCC patients compared with healthy controls both in the training and test cohorts (pu2009<u20090.01). The combination of miR-652 and miR-660 exhibited significantly higher AUC than miR-660, CEA and CA125 for ADC and SCC diagnosis in both the training and test cohorts (pu2009<u20090.05). Furthermore, miR-652u2009+u2009miR-660u2009+u2009Cyfra21-1 significantly improved the diagnostic ability to determine ADC patients from healthy controls. For SCC diagnosis, miR-652u2009+u2009miR-660u2009+u2009Cyfra21-1 exhibited comparable ability to Cyfra21-1. The results indicate that the combination of miR-652u2009+u2009miR-660 and Cyfra21-1 has the potential to help in the diagnosis of NSCLC, especially for ADC.

Identification of somatic alterations in stage I lung adenocarcinomas by next-generation sequencing

Adenocarcinoma is the most common type of lung cancer. Somatic mutations in the early stage of this disease have a tight relationship with tumor initiation and potentially activate downstream pathways that are implicated in tumor progression. In this study, we performed whole genome and exome sequencing of tumor and adjacent normal tissue from 10 patients with stage I lung adenocarcinoma. EGFR (4/10 tumors), BCHE (3/10), and TP53 (2/10) were identified recurrently with validated tumor‐specific non‐synonymous mutations; and the remaining mutations were specific to individual tumors. Computational methods were used to evaluate the potential effect of non‐synonymous mutations on protein function, and putative driver mutation in genes such as SDK1 was predicted. Cell adhesion was the most enriched biological process in gene set analysis using the DAVID database. Copy number amplification at 12q15, which includes MDM2, was identified as a recurrent somatic alteration in 4 of 10 tumors. These findings provided additional information for understanding early‐stage lung adenocarcinomas.

Stair-Climbing Test Predicts Postoperative Cardiopulmonary Complications and Hospital Stay in Patients with Non-Small Cell Lung Cancer

Background There is currently no reliable method to predict major postoperative cardiopulmonary complications for patients with non-small cell lung cancer (NSCLC). In this study, we hypothesized that exercise oxygen desaturation (EOD) and heart rate change results in a stair-climbing test (SCT) would predict postoperative cardiopulmonary complications for patients with NSCLC. Material/Methods We examined 171 patients (41 females and 130 males) with NSCLC by preoperative SCT from January 2010 to July 2015. Among them, 27 underwent wedge resection, 122 underwent lobectomy, and 22 underwent pneumonectomy. The correlation between postoperative cardiopulmonary complications and parameters of SCT and pulmonary function test (PFT) parameters were analyzed retrospectively. Results The overall 30-day postoperative morbidity of the patients was 46/171 (26.9%), with death occurring in 3/171(1.8%). The age, FEV1%, MVV, height of climbing, EOD, and heart rate change were found to be significantly different between the group with postoperative cardiopulmonary complications and those without. Binary logistic regression analysis showed that EOD and heart rate change were independently correlated with postoperative cardiopulmonary complications. In addition, a model predicting the probability of postoperative cardiopulmonary complication based on logistic regression for multivariable analysis was used to confirm our findings. Conclusions A symptom-limited SCT with oxygen saturation monitoring is a safe, simple, and low-cost method to evaluate cardiopulmonary function preoperatively.

Development and validation of clinical diagnostic models for the probability of malignancy in solitary pulmonary nodules

It is critical to develop a non‐invasive and accurate method for differentiating between malignant and benign solitary pulmonary nodules. In large sample studies, the effectiveness of the diagnostic prediction model as a tool of assessment of the probability of malignancy is still unclear. The establishment of a diagnostic model based on large samples is needed.

Novel long noncoding RNA NMR promotes tumor progression via NSUN2 and BPTF in esophageal squamous cell carcinoma

Long noncoding RNAs (lncRNA) have been implicated in cancer but most of them remain largely unstudied. Here, we identified a novel NSUN2 methylated lncRNA (NMR), which was significantly upregulated in esophageal squamous cell carcinoma (ESCC), functioned as a key regulator of ESCC tumor metastasis and drug resistance. Upregulation of NMR correlated with tumor metastasis and indicated poor overall survival in ESCC patients. Functionally, NMR could promote tumor cell migration and invasion, inhibit cisplatin-induced apoptosis and increase drug resistance in ESCC cells. Mechanistically, transcription of NMR could be upregulated by NF-κB activation after IL-1β and TNF-α treatment. NMR was methylated by NSUN2 and might competitively inhibit methylation of potential mRNAs. NMR could directly bind to chromatin regulator BPTF, and potentially promote MMP3 and MMP10 expression by ERK1/2 pathway through recruiting BPTF to chromatin. Taken together, NMR functions as an oncogenic gene and may serve as new biomarker and therapeutic target in ESCC.

Blind spot in lung cancer lymph node metastasis: Cross-lobe peripheral lymph node metastasis in early stage patients: Cross-lobe lymph node metastasis in LC

At present, it has not yet been determined whether metastasis can be transferred cross‐lobe to peripheral lymph nodes (LNs) from other lobes in early stages of lung cancer, especially without any direct involvement to the pleura and parenchyma of the lobe. This study was conducted to investigate this issue.