Zongbin Xu

sMicroRNA-1290 inhibits cells proliferation and migration by targeting FOXA1 in gastric cancer cells.

BACKGROUND/AIMS Gastric cancer is the third leading cause of cancer-related deaths in the world with high mortality rate due to the lack of markers in early detection and effective therapies. MicroRNAs (miRNAs), a critical part of epigenetic regulations in tumor, have been shown to be closely related to the initiation, development, invasion, metastasis and prognosis of gastric cancer. The present study aims to investigate the expression of miR-1290 in gastric tumor cells and to elucidate the target gene of miR-1290 in SGC-7901 gastric cancer cells. METHODOLOGY The fluorescence in situ hybridization, real time PCR and Western blot were used to investigate the expression of miR-1290 in gastric tumor cells and clinical gastric tumor samples. The effect of miR-1290 expression on gastric tumor cells was studied using Synthetic miR-1290 inhibitor transfection, in vitro wound healing assay and flow cytometry analysis. Bioinformatics and Luciferase reporter assay were used to predict and validate the target gene of miR-1290. RESULTS Our results revealed that miR-1290 was highly expressed in SGC-7901 gastric cancer cells as well as in clinical gastric cancer samples, which was correlated with clinical stages, depth of invasion and lymph node metastasis. Synthetic miR-1290 inhibitor transfection significantly inhibited the proliferation and migration of SGC-7901 cells. Bioinformatics analysis and luciferase reporter assay suggested that miR-1290 functioned in gastric cancer cells by targeting FOXA1 gene. CONCLUSION miR-1290 promotes gastric tumor cells proliferation and metastasis through FOXA1, which could be used as a marker for diagnosis and a target for therapeutic intervention.

Lentivirus-mediated RNA interference targeting WWTR1 in human colorectal cancer cells inhibits cell proliferation in vitro and tumor growth in vivo

WW domain-containing transcription regulator 1 (WWTR1) was initially identified as a transcriptional coactivator involved in the differentiation of stem cells as well as the development of multiple organs. Recently, WWTR1 has also been identified as a major component of the novel Hippo signalling pathway important for the development of breast and lung cancer. Here, we show for the first time that WWTR1 has an oncogenic function in colorectal cancer cell lines. Knockdown of WWTR1 by lentivirus-mediated RNA interference in human colorectal cancer cells significantly decreased cell proliferation and the colony formation of RKO cells in vitro and tumor growth in vivo. Furthermore, we found that the decreased proliferation was due to cell cycle arrest and increased apoptosis. In addition, efficient knockdown of WWTR1, demonstrated by quantitative real-time PCR, led to upregulation of ASNS and downregulation of SMAD3, LTBR, BAX and BAK1 in WWTR1 knockdown cells, suggesting that these genes may be involved in the repression of cell proliferation. Our findings indicate that WWTR1 is an oncogene and has an important role in the proliferation of colorectal cancer cells and in tumor growth in vivo.

Genetic polymorphisms in translesion synthesis genes are associated with colorectal cancer risk and metastasis in Han Chinese.

Translesion synthesis (TLS) polymerases have low processivity and fidelity compared with replicative polymerases. Defective function of TLS polymerases result in chromosome instability. The aim of this study was to evaluate the effects of TLS genes on susceptibility and metastasis in colorectal cancer (CRC). Four single nucleotide polymorphisms (SNPs) (rs462779, rs11153292, rs373572 and rs2233004) of TLS genes were genotyped in the pilot cohort consisted of 516 patients with CRC and 503 controls, and then replicated in the replication cohort of 421 cases and 446 controls. The genotype frequencies of rs462779 and rs373572 were significantly different between CRC patients and controls in both two cohorts, even after it was adjusted by age, gender and smoking status. Stratified analysis showed that rs462779 and rs373572 were significantly associated with both colon and rectum cancer. In patients with metastatic CRC, the frequency of AA genotype of rs373572 was significantly increased as compared with those without metastasis CRC (P=0.001). Furthermore, rs462779 and rs373572 exhibited remarkably cumulative effect on the risk of CRC (trend P value=0.001). No significant difference was observed between other SNPs and CRC. These results suggest that polymorphisms in TLS genes are associated with susceptibility to CRC in Chinese and might be a novel biomarker for the predication of metastasis risk of CRC.

A nomogram predicting pathological complete response to neoadjuvant chemoradiotherapy for locally advanced rectal cancer: implications for organ preservation strategies

PURPOSE To determine predictors of pathological complete response (pCR) in locally advanced rectal cancer patients treated with neoadjuvant chemoradiotherapy (nCRT), and develop a predictive nomogram. METHODS A total of 522 locally advanced rectal cancer patients undergoing nCRT and curative resection between 2008 and 2014 were included. Uni- and multivariate analysis was performed to identify predictors of pCR. A nomogram was developed and validated by internal (n=425) and external validation (n=97). RESULTS With a median follow-up of 55 months, pCR was associated with better 5-year overall and disease-free survival, distant control, but similar local control. Logistic regression showed that post-CRT distance from the anal verge (OR =0.840, P = 0.022), post-CRT tumor size (OR = 0.565, P = 0.003), post-CRT circumferential extent of tumor (OR = 0.021, P < 0.001), pre-CRT CEA level (OR = 2.004, P = 0.033), and post-CRT CEA level (OR = 3.767, P = 0.038) were independently associated with pCR. A nomogram was developed with a C-index of 0.81 and 0.75 on internal and external validation, respectively. CONCLUSION pCR was associated with better long-term outcome. A nomogram was successfully developed to predict pCR. It could support decision-making in organ preservation strategies.Purpose To determine predictors of pathological complete response (pCR) in locally advanced rectal cancer patients treated with neoadjuvant chemoradiotherapy (nCRT), and develop a predictive nomogram. Methods A total of 522 locally advanced rectal cancer patients undergoing nCRT and curative resection between 2008 and 2014 were included. Uni- and multivariate analysis was performed to identify predictors of pCR. A nomogram was developed and validated by internal (n=425) and external validation (n=97). Results With a median follow-up of 55 months, pCR was associated with better 5-year overall and disease-free survival, distant control, but similar local control. Logistic regression showed that post-CRT distance from the anal verge (OR =0.840, P = 0.022), post-CRT tumor size (OR = 0.565, P = 0.003), post-CRT circumferential extent of tumor (OR = 0.021, P < 0.001), pre-CRT CEA level (OR = 2.004, P = 0.033), and post-CRT CEA level (OR = 3.767, P = 0.038) were independently associated with pCR. A nomogram was developed with a C-index of 0.81 and 0.75 on internal and external validation, respectively. Conclusion pCR was associated with better long-term outcome. A nomogram was successfully developed to predict pCR. It could support decision-making in organ preservation strategies.

A nomogram to predict distant metastasis after neoadjuvant chemoradiotherapy and radical surgery in patients with locally advanced rectal cancer

To compare distant metastasis (DM) in locally advanced rectal cancer (LARC) patients treated with neoadjuvant chemoradiotherapy (nCRT) and surgery alone, and to develop a predictive nomogram for DM following nCRT.

Knockdown of KLK11 inhibits cell proliferation and increases oxaliplatin sensitivity in human colorectal cancer.

It has been reported that kallikrein 11 (KLK11) is crucially involved in the development and progression of various types of cancer. However, the molecular mechanisms that underlie the involvement of KLK11 in aberrant colorectal cancer (CRC) cell growth remain largely unclear. The aim of the present study was to investigate the role of KLK11 and the effects of KLK11 on oxaliplatin (L-OHP) chemosensitivity by knocking down KLK11 in LOVO and HCT-8 cells. Loss-of-function assays revealed KLK11 inhibition significantly inhibited growth and induced apoptosis of CRC cells in vitro. Notably, further experiments found that knockdown of KLK11 expression increased the L-OHP chemosensitivity of CRC cells. KLK11 inhibition of increased L-OHP-induced apoptosis may be associated with activation of caspase-3 cleavage and the apoptosis signaling pathway. The present results indicated that KLK11 may be an potential target of interest for future research into therapies for CRC.

Knockdown of KLK11 reverses oxaliplatin resistance by inhibiting proliferation and activating apoptosis via suppressing the PI3K/AKT signal pathway in colorectal cancer cell

Introduction Kallikrein 11 (KLK11) plays a crucial role in drug-resistance to oxaliplatin (L-OHP) in the treatment of metastatic colorectal cancer (mCRC). The study aimed to investigate the role of KLK11 in chemoresistance, and to clarify the mechanism underlying reverse of L-OHP resistance by knockdown of KLK11. Materials and Methods Resistance to oxaliplatin was induced in HCT-8 (HCT-8/L-OHP) colorectal adenocarcinoma cell lines by exposing cells to increasing concentrations of L-OHP. MTT, RT-qPCR, and Western blot were used to evaluate the resistance to L-OHP. We then knocked down KLK11 in HCT-8/L-OHP cells to explore the mechanism through which KLK11 reverses L-OHP resistance. The mRNA and protein expression of KLK11 in tissues from mCRC patients were detected by RT-qPCR and immunohistochemistry. Results The drug resistance index (RI) of HCT-8/L-OHP cell line to L-OHP, 5-Fluorouracil (5-FU), Irinotecan (CPT-11), Vincristine (VCR) and Cis-diamminedichloroplatinum (CDDP) were 10, 5.35, 3.23, 1.28, and 6.64, respectively. Increased expression of multi-drug resistant genes ABCC1, ABCB1, GSTP1 and ERCC1 were detected in HCT-8/L-OHP cell line. Moreover, the activated PI3K/AKT pathway was related to L-OHP-resistance. Knockdown of KLK11 in HCT-8/L-OHP cell reversed L-OHP-resistance by inhibiting cell growth and activating apoptosis via suppressing the PI3K/AKT signaling pathway. Moreover, high expression of KLK11 in chemoresistant-patients was associated with lymph node metastases and histopathology. Conclusion KLK11 was highly expressed in chemoresistant-patients and L-OHP-resistant cell lines. Moreover, L-OHP resistance was associated with activated PI3K/AKT signal pathway. Knockdown of KLK11 can reverse L-OHP resistance by blocking PI3K/AKT signaling pathway.

Prognostic significance of neoadjuvant rectal score in locally advanced rectal cancer after neoadjuvant chemoradiotherapy and construction of a prediction model.

To evaluate the prognostic significance of neoadjuvant rectal (NAR) score after neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer (LARC), and to develop a nomogram predicting disease‐free survival (DFS).

Risk Factors for Early Postoperative Small Bowel Obstruction after Elective Colon Cancer Surgery: An Observational Study of 1,244 Consecutive Patients

Background: Early postoperative small bowel obstruction (EPSBO) is a common complication following colon cancer surgery. EPSBO is associated with increased hospital stays, mortality rates, and healthcare costs. The purpose of this study was to identify risk factors for EPSBO following elective colon cancer surgery. Study Design: We retrospectively reviewed the clinicopathological variables of 1,244 patients with colon cancer who underwent partial colectomy from January 2000 to December 2014. A multivariable logistic regression model was used to identify risk factors for EPSBO. Results: The EPSBO rate was 3.5%. In multivariate analysis, preoperative bowel obstruction (OR 2.378; 95% CI 0.986-5.735, p = 0.054), weight loss >10% of body weight (OR 3.029; 95% CI 1.000-9.178, p = 0.05), albumin level (in g/L; OR 0.966; 95% CI 0.937-0.996, p = 0.024), and surgical duration (in min; OR 1.008; 95% CI 1.003-1.012, p = 0.003) were significant predictors of EPSBO. Conclusion: EPSBO is more likely to develop in the presence of poor systemic conditions (e.g., weight loss >10% of body weight, hypoalbuminemia, and preoperative bowel obstruction) and following operations of longer duration. These predictors may facilitate the stratification of patients at risk for EPSBO following surgery for elective colon cancer.

A scoring system basing pathological parameters to predict regional lymph node metastasis after preoperative chemoradiotherapy for locally advanced rectal cancer: implication for local excision.

Local excision is an alternative to radical surgery that is indicated in patients with locally advanced rectal cancer (LARC) who have a good response to chemoradiotherapy (CRT). Regional lymph node status is a major uncertainty during local excision of LARC following CRT. We retrospectively reviewed clinicopathologic variables for 244 patients with LARC who were treated at our institute between December 2000 and December 2013 in order to identify independent predictors of regional lymph node metastasis. Multivariate analysis of the training sample demonstrated that histopathologic type, tumor size, and the presence of lymphovascular invasion were significant predictors of regional nodal metastasis. These variables were then incorporated into a scoring system in which the total scores were calculated based on the points assigned for each parameter. The area under the curve in the receiver operating characteristic analysis was 0.750, and the cutoff value for the total score to predict regional nodal metastasis was 7.5. The sensitivity of our system was 73.2% and the specificity was 69.4%. The sensitivity was 77.8% and the specificity was 51.2% when the scoring system was applied to the testing sample. Using this system, we could accurately predict regional nodal metastases in LARC patients following CRT, which may be useful for stratifying patients in clinical trials and selecting potential candidates for organ-sparing surgery following CRT for LARC