Qingchuan Zhao

The prognostic and chemotherapeutic value of miR-296 in esophageal squamous cell carcinoma.

Objective:We aimed first to investigate the expression pattern of miRNAs in esophageal squamous cell cancer and then compared it with those of adjacent benign esophageal tissues. The role of target miRNAs in the development of esophageal cancer was further detected. Summary Background Data:Although esophageal squamous cell carcinoma was of high incidence in China, the pathogenic mechanism remained largely unknown. A better understanding of changes in miRNA expression during esophageal carcinogenesis might lead to possible improvements in the diagnosis and treatment for esophageal carcinoma. Methods:The miRNAs were identified differentially expressed in esophageal cancer tissues, using miRNA microarray, real-time PCR, and Northern blot. The role of target miRNAs was investigated by in vitro and in vivo assay. Results:Nine miRNAs with increased expression and 3 with decreased expression were identified. The expression of miR-296 was found increasingly up-regulated in esophagitis tissues, esophageal carcinoma in situ, and esophageal squamous cell cancer tissues. Low expression of miR-296 was able to distinguish long-term survivors with node-positive disease from those dying within 20 months by predicting survival (median, 23.7 vs. 12.9 months). Downregulation of miR-296 might inhibit growth of esophageal cancer cells in vitro and in vivo through regulation of cyclin D1 and p27. Downregulation of miR-296 could confer sensitivity of both P-glycoprotein-related and P-glycoprotein-nonrelated drugs on esophageal cancer cells, and might promote ADR-induced apoptosis, accompanied by increased accumulation and decreased releasing amount of ADR. Downregulation of miR-296 could significantly decrease the expression of P-glycoprotein, Bcl-2, and the transcription of MDR1, but up-regulate the expression of Bax. Conclusions:MiR-296 might play important roles in the pathogenesis of esophageal cancer and considered as a potential target for this malignancy intervention.

MicroRNA‐107, an oncogene microRNA that regulates tumour invasion and metastasis by targeting DICER1 in gastric cancer

MicroRNAs are small non‐coding RNA molecules that control expression of target genes. Previous studies showed that microRNA‐107 (miR‐107) is overexpressed in gastric cancer tissues compared with the matched normal tissues. However, it remains largely unclear as to how miR‐107 exerts its function and modulates the malignant phenotypes of gastric cancer, because our understanding of miR‐107 signalling pathways is limited. In this study, we demonstrate that miR‐107 is frequently up‐regulated in gastric cancers and its overexpression is significantly associated with gastric cancer metastasis. Furthermore, silencing the expression of miR‐107 could inhibit gastric cancer cell migration and invasion in vitro and in vivo. Subsequent investigation characterized DICER1 as a direct target of miR‐107. Up‐regulation of DICER1 resulted in a dramatic reduction of in vitro migration, invasion, in vivo liver metastasis of nude mice, which is similar to that occurs with the silencing of miR‐107, indicating that DICER1 functions as a metastasis suppressor in gastric cancer. Furthermore, the restoration of DICER1 can inhibit miR‐107‐induced gastric cancer cell invasion and metastasis. In conclusion, our results suggested that miR‐107, an oncogene miRNA promoting gastric cancer metastasis through down‐regulation of DICER1. Inhibition of miR‐107 or restoration of DICER1 may represent a new potential therapeutic target for gastric cancer treatment.

Long Noncoding RNA MRUL Promotes ABCB1 Expression in Multidrug-Resistant Gastric Cancer Cell Sublines

ABSTRACT Multidrug resistance (MDR) is the most common cause of chemotherapy failure in gastric cancer (GC) treatment; however, the underlying molecular mechanisms remain elusive. Long noncoding RNAs (lncRNAs) can be involved in carcinogenesis, but the effects of lncRNAs on MDR are poorly understood. We show here that the lncRNA MRUL (MDR-related and upregulated lncRNA), located 400 kb downstream of ABCB1 (ATP-binding cassette, subfamily B, member 1), was significantly upregulated in two multidrug-resistant GC cell sublines, SGC7901/ADR and SGC7901/VCR. Furthermore, the relative expression levels of MRUL in GC tissues were negatively correlated with in vitro growth inhibition rates of GC specimens treated with chemotherapeutic drugs and indicated a poor prognosis for GC patients. MRUL knockdown in SGC7901/ADR and SGC7901/VCR cells led to increased rates of apoptosis, increased accumulation, and reduced doxorubicin (Adriamycin [ADR]) release in the presence of ADR or vincristine. Moreover, MRUL depletion reduced ABCB1 mRNA levels in a dose- and time-dependent manner. Heterologous luciferase reporter assays demonstrated that MRUL might positively affect ABCB1 expression in an orientation- and position-independent manner. Our findings indicate that MRUL promotes ABCB1 expression and is a potential target to reverse the MDR phenotype of GC MDR cell sublines.

NEAT expression is associated with tumor recurrence and unfavorable prognosis in colorectal cancer.

Long noncoding RNAs (lncRNAs) have recently been identified to be involved in various diseases including cancer. NEAT1 is a recently identified lncRNA with its function largely unknown in human malignancy. In the present study, we investigated NEAT1 expression in 239 cases of clinical colorectal cancer specimens and matched normal tissues. Statistical methods were utilized to analyze the association of NEAT1 with clinical features, disease-free and overall survival of patients. Results showed that NEAT1 expression in colorectal cancer was up-regulated in 72.0% (172/239) cases compared with corresponding normal counterparts, and related to tumor differentiation, invasion, metastasis and TNM stage. Kaplan-Meier analysis proved that NEAT1 was associated with both disease-free survival and overall survival of patients with colorectal cancer that patients with high NEAT1 expression tend to have unfavorable outcome. Moreover, cox’s proportional hazards analysis showed that high NEAT1 expression was an independent prognostic marker of poor outcome. These results provided the first evidence that the expression of NEAT1 in colorectal cancer may play an oncogenic role in colorectal cancer differentiation, invasion and metastasis. It also proved that NEAT1 may serve as an indicator of tumor recurrence and prognosis of colorectal cancer.

MicroRNA-21: a therapeutic target for reversing drug resistance in cancer

Introduction: Drug resistance is a major clinical obstacle to the successful treatment of human cancer. The microRNAs-21 (miR-21), an oncomiR, may play an important role in the progress of drug resistance. Areas covered: This review covers all related literature on miR-21 in drug resistance of human cancers and analyzes the expression, biological functions and targets of it. This study also envisages future developments toward its clinical and therapeutic applications in cancer treatment. Expert opinion: The miR-21 may promote the drug resistance of various cancers. Inhibitors of miR-21 may function as effective approaches for reversing drug resistance in cancer cells. There is a tough way from discovering the function of miR-21 to clinical use. Further understanding of miR-21-mediated signaling pathways will help to promote the therapeutic–clinical use of miR-21 in cancer.

Fast-track surgery could improve postoperative recovery in radical total gastrectomy patients

AIM To assess the impact of fast-track surgery (FTS) on hospital stay, cost of hospitalization and complications after radical total gastrectomy. METHODS A randomized, controlled clinical trial was conducted from November 2011 to August 2012 in the Department of Digestive Surgery, Xijing Hospital of Digestive Diseases, the Fourth Military Medical University. A total of 122 gastric cancer patients who met the selection criteria were randomized into FTS and conventional care groups on the first day of hospitalization. All patients received elective standard D2 total gastrectomy. Clinical outcomes, including duration of flatus and defecation, white blood cell count, postoperative pain, duration of postoperative stay, cost of hospitalization and complications were recorded and evaluated. Two specially trained doctors who were blinded to the treatment were in charge of evaluating postoperative outcomes, discharge and follow-up. RESULTS A total of 119 patients finished the study, including 60 patients in the conventional care group and 59 patients in the FTS group. Two patients were excluded from the FTS group due to withdrawal of consent. One patient was excluded from the conventional care group because of a non-resectable tumor. Compared with the conventional group, FTS shortened the duration of flatus (79.03 ± 20.26 h vs 60.97 ± 24.40 h, P = 0.000) and duration of defecation (93.03 ± 27.95 h vs 68.00 ± 25.42 h, P = 0.000), accelerated the decrease in white blood cell count [P < 0.05 on postoperative day (POD) 3 and 4], alleviated pain in patients after surgery (P < 0.05 on POD 1, 2 and 3), reduced complications (P < 0.05), shortened the duration of postoperative stay (7.10 ± 2.13 d vs 5.68 ± 1.22 d, P = 0.000), reduced the cost of hospitalization (43783.25 ± 8102.36 RMB vs 39597.62 ± 7529.98 RMB, P = 0.005), and promoted recovery of patients. CONCLUSION FTS could be safely applied in radical total gastrectomy to accelerate clinical recovery of gastric cancer patients.

Astrocytic activation in thoracic spinal cord contributes to persistent pain in rat model of chronic pancreatitis

One of the most important symptoms in chronic pancreatitis (CP) is constant and recurrent abdominal pain. However, there is still no ideal explanation and treatment on it. Previous studies indicated that pain in CP shared many characteristics of neuropathic pain. As an important mechanism underlying neuropathic pain, astrocytic activation is probably involved in pain of CP. Based on the trinitrobenzene sulfonic acid (TNBS)-induce rat CP model, we performed pancreatic histology to assess the severity of CP with semiquantitative scores and tested the nociceptive behaviors following induction of CP. Glial fibrillary acidic protein (GFAP) expressions in the thoracic spinal cord were observed by immunohistochemistry and real-time reverse transcription polymerase chain reaction (RT-PCR). Meanwhile, we injected intrathecally astrocytic specific inhibitor l-alpha-aminoadipate (LAA) and observed its effect on nociception induced by CP. Compared to the naive and sham group, TNBS produced long lasting pancreatitis, and persistent mechanical hypersensitivity in the abdomen that was evident 1 week after TNBS infusion and persisted up to 5 weeks. Compared with naive or sham operated rats, GFAP staining was significantly increased 5 weeks after CP induction. Real-time RT-PCR indicated that GFAP expression was significantly increased in TNBS treated rats compared to the sham group. TNBS-induced astrocytic activation was significantly attenuated by LAA, compared with the saline control. Treatment with LAA significantly, even though not completely, attenuated the allodynia. Our results provide for the first time that astrocytes may play a critical role in pain of CP. Some actions could be taken to prevent astrocytic activation to treat pain in CP patients.

Matrix Metalloproteinase-9 Is Associated with Relapse and Prognosis of Patients with Colorectal Cancer

BackgroundMatrix metalloproteinase-9 is a member of the MMP family, which is overexpressed in some solid tumors and is thought to enhance tumor invasion and metastasis ability. The present study aims to examine MMP-9 expression in human colorectal cancer and to determine its association with clinicopathological characteristics and prognosis.MethodsColorectal cancer and adjacent normal tissues from 192 patients were investigated by immunohistochemical assay. Staining evaluation results were analyzed statistically in relation to various clinicopathological characters, disease-free survival, and overall survival.ResultsHigh level of MMP-9 expression was detected in colorectal cancer, significantly more than in normal colorectal epithelial cells. In colorectal cancer, MMP-9 was significantly positively correlated with depth of invasion, lymph node metastasis, and distant metastasis. However, no correlations between MMP-9 expression and patient age, sex, tumor location or differentiation status were detected. Disease-free and overall survival were significantly poorer for patients with positive MMP-9 staining than for those with MMP-9-negative tumors.ConclusionsOur findings emphasize the important role of MMP-9 in the invasion and metastasis process in human colorectal cancer. It could also serve as a novel prognostic marker that is independent of, and additive to, the tumor–node–metastasis (TNM) staging system.

Overweight Is an Additional Prognostic Factor in Acute Pancreatitis: A Meta-Analysis

Background/Aims: It is generally accepted that there is a correlation between obesity and poor outcome in acute pancreatitis (AP); however, the relationship between overweight and the prognosis of AP is unknown. The aim of this study was to determine the correlation between overweight and the prognosis of AP. Methods: MEDLINE and PubMed were searched using the terms ‘acute pancreatitis’, ‘obesity’, ‘overweight’, and ‘body mass index’ (‘BMI’). All prospective clinical studies correlating BMI and AP were included. Obesity and overweight were defined as BMI ≧30 and from 25 to 30, respectively. A meta-analysis was performed with the endpoints severe AP (SAP), local complications, systemic complications, and mortality. Results: Eight studies including 939 patients were found. The incidence rates of SAP (OR 2.48, 95% CI 1.34–4.60), local complications (OR 2.58, 95% CI 1.20–5.57), and mortality (OR 3.81, 95% CI 1.22–11.83) were increased in overweight patients with AP. No difference was detected in the incidence of systemic complications between the normal-weight and overweight patients (OR 1.62, 95% CI 0.76–3.43). In addition, the correlation between obesity and poor prognosis was again confirmed. Conclusion: Overweight is an additional prognostic factor of severity, local complications, and mortality in AP.

Expression of NDRG2 in esophageal squamous cell carcinoma

N‐Myc downstream‐regulated gene 2 (NDRG2), a new member of the N‐Myc downstream‐regulated gene family, has been found to be a differentially expressed gene involved in a variety of cancers. The present study aimed to investigate the expression of NDRG2 in esophageal squamous cell carcinoma (ESCC). Immunohistochemistry was performed in 154 samples from patients with ESCC to detect the expression level of NDRG2 and C‐MYC. Results indicated that the expression level of NDRG2 in the cancer samples was significantly lower than that in normal tissues; the trend of C‐MYC was the reverse. The Wilcoxon–Mann–Whitney test showed significant difference in the expression of NDRG2 in patients with different T stage, TNM stage, and differentiation degree of cancers (P = 0.036, 0.031, 0.001, respectively). Patients in stages I and II were followed up for 5 consecutive years and Kaplan–Meier survival analysis demonstrated that the survival time of ESCC patients with high expression of NDRG2 was longer than those with low expression during the 5‐year follow‐up period (P = 0.0018). Cox regression analysis indicated that low expression of NDRG2, cancer stage of pT1, and distant organ metastasis (pM1) were the independent poor prognostic factors of ESCC (P = 0.004, 0.019, 0.0013, respectively). Furthermore, up‐regulation of NDRG2 was introduced to ESCC cell lines (EC9706 and EC109) by plasmid transfection. In vivo and in vitro studies indicated that overexpression of NDRG2 markedly reduced proliferation and promoted the apoptosis of EC9706 and EC109 cells. In summary, our results demonstrated that NDRG2 played an important role in the proliferation of ESCC cells and the expression of NDRG2 in ESCC was closely related with the prognosis.