Ren Zhao

Expression of Cortactin Correlates with a Poor Prognosis in Patients with Stages II–III Colorectal Adenocarcinoma

BackgroundThe present study was designed to specifically investigate the clinicopathological role of expression of cortactin, as well as the correlation with clinical outcomes in stages II–III colorectal cancer (CRC).MethodsTwo hundred and five stages II–III CRC patients were included in this study. Formalin-fixed paraffin-embedded specimens were stained for cortactin and the correlation between the staining, its clinicopathological parameters, and its prognostic power were analyzed statistically.ResultsOf the 205 patients studied, 113 cases (55.1%) were strongly positive for cortactin. Cortactin expression correlated with tumor invasion (P = 0.018), histological grade (P = 0.004), and preoperative CEA level (P < 0.001). In univariate analysis, tumor invasion, American Joint Committee on Cancer (AJCC) stage, lymphovascular invasion, preoperative CEA level, and cortactin expression were significant prognostic factors for disease-free survival (P = 0.034, 0.009, 0.043, 0.004, and 0.004, respectively), while for overall survival, tumor invasion, AJCC stage, pathologic grade, preoperative CEA level, and cortactin expression were significant prognostic factors (P = 0.003, 0.008, 0.038, 0.017, and <0.001, respectively). In multivariate analysis, tumor invasion, preoperative CEA level, and cortactin expression maintained their independent prognostic influence on disease-free survival (P = <0.001, 0.003, and 0.008, respectively). However, tumor invasion, AJCC stage, and cortactin expression influenced overall survival (P = 0.036, <0.001, and 0.004, respectively).ConclusionsCortactin may be a good biomarker to be applied in the clinical setting to predict the prognosis of patients with completely resected pathologic stages II–III CRC.

CHD1L promotes tumor progression and predicts survival in colorectal carcinoma.

BACKGROUND To evaluate the expression of chromodomain helicase/adenosine triphosphatase DNA binding protein 1-like gene (CHD1L) in colorectal carcinoma (CRC) and its clinical significance. Its oncogenic ability was also investigated. MATERIALS AND METHODS CHD1L amplification and overexpression were detected by fluorescence in situ hybridization, real-time reverse transcriptase-polymerase chain reaction, and immunohistochemistry in 86 patients with CRC. The correlation between the clinical characteristics and prognosis was also determined. To evaluate the tumorigenic ability of CHD1L, it was cloned into expression vector pcDNA3.1(+) and transfected into CRC cell line SW1116. Next, the changes in the biologic behavior of the CRC cells, including cell proliferation, adhesion, migration, and invasion, were examined. Apoptosis and the cell cycle of the CRC cells were detected using flow cytometry. RESULTS We have demonstrated that CHD1L is frequently amplified and overexpressed in CRC. Overexpression of CHD1L correlated with a large tumor size, deep tumor invasion, and a high histologic grade. It also conferred worse disease-free survival. CHD1L-transfected cells possessed a strong oncogenic ability, increasing the tumorigenicity in nude mice, which could be effectively suppressed by small interfering RNA against CHD1L. Functional studies showed that overexpression of CHD1L could promote G1/S-phase cells and inhibit apoptosis. CONCLUSIONS Our results suggest that CHD1L is the target oncogene within the 1q21 amplicon and plays a pivotal role in CRC pathogenesis.

A Phase II Study of Irinotecan and Capecitabine for Patients with Unresectable Liver-only Metastases from Colorectal Cancer

OBJECTIVE To assess the resectability rate of patients with initially unresectable liver-only metastases from colorectal cancer (CRC) after treatment with irinotecan/capecitabine. METHODS Patients received irinotecan (240 mg/m(2)) as a 30 min intravenous infusion on day 1 and capecitabine (1000 mg/m(2)) orally bid for 14 days beginning on day 2. Treatment was repeated every 3 weeks. The protocol encouraged two to four cycles of irinotecan/capecitabine after recovery from surgery. RESULTS Between May 2004 and February 2007, 48 patients entered in the study. Forty-seven (97.9%) of the 48 patients were assessable for response. The overall response rate before surgery was 56.3% (95% CI, 42.3-70.3%) in the treated population, including 2 non-confirmed complete response (CR), 18 partial responses (PR) and 7 non-confirmed PR. Twenty-three (47.9%) of 29 patients with tumor shrinkage proceeded to surgical intervention. Twenty of the 23 patients had a complete resection (S-CR). With a median follow-up time of 32 months (range, 24-38 months), the overall median time to progression and overall survival for all patients were 16.7 months (95% CI, 10.0-23.4 months) and 27.5 months (95% CI, 23.6-31.4 months) for all patients. The 1- 2- and 3-year overall survival estimates were 79.2% (95% CI, 67.7-90.7%), 60.4% (95% CI, 46.6-74.3%) and 29.2% (95% CI, 16.3-42.0%), respectively. Grade 3 diarrhea occurred in eight (17.0%) patients. The most common Grade 3/4 hematological adverse event was neutropenia in 8.5% of the patients. There were no treatment-related deaths during this study. CONCLUSIONS Irinotecan/capecitabine appears to be a safe and very effective regimen in selected patients with unresectable liver metastases from CRC, but who are treated with a curative intent.

Expression and Clinical Significance of L-Plastin in Colorectal Carcinoma

Introductionl-plastin, an actin-binding protein, is upregulated in many tumours, including colorectal carcinoma. This study evaluated the expression of l-plastin in plasma and colorectal tumour tissue and analysed the correlation between clinicopathological staging and prognosis.Materials and MethodsEnzyme-linked immunosorbent assay was used to detect l-plastin in the plasma of 120 colorectal carcinoma patients and 40 control subjects. Immunohistochemistry analyses were also used.ResultsThe rate of positive l-plastin expression was significantly higher in colorectal carcinoma patients than in control subjects, and was significantly higher in tumour tissues than in the tissues surrounding the tumour. l-Plastin expression also is correlated with tumour grade and size, and lymph node metastasis. However, there was no correlation with the extent of tumour invasion or distant metastasis.Conclusionl-Plastin may be a useful marker for screening colorectal carcinoma and determining the prognosis of patients with colorectal carcinoma, and for genetic therapy and targeted therapy of colorectal carcinoma.

MLLT10 promotes tumor migration, invasion, and metastasis in human colorectal cancer

Abstract Objectives: Colorectal cancer (CRC), one of the most aggressive gastrointestinal malignancies, is a frequently diagnosed life-threatening cancer worldwide. Most CRC patients have poor prognosis mainly because of frequent metastasis and recurrence. Thus, it is crucial to find out some new biomarkers and to show deeper insights into the mechanisms of CRC. MLLT10, Myeloid/lymphoid or mixed-lineage leukemia translocated to 10, also known as AF10, a recurrent MLL partner. In this study, we found that MLLT10 promotes CRC tumor invasion and metastasis both in vitro and in vivo. Methods: Here, the expression of MLLT10 was evaluated by immunohistochemistry. Then, the plasmid and lentivirus particles for MLLT10 overexpression or knockdown were designed and constructed into SW620 and HT29 cells. Finally, cell proliferation assay, cell adhesion assay, transwell migration, and invasion assay were used to detect the migration and invasion ability of MLLT10 in CRC cells. A tail vein injection assay was employed to evaluate the role of MLLT10 in tumor metastases. Results: MLLT10 expression was significantly higher in CRC tissues than in noncancerous tissues and was associated with some clinicopathological factors. In vitro, the overexpression of MLLT10 promoted CRC cell migration and invasion, while after MLLT10 was knocked down, the opposite results were observed. Furthermore, we used animal metastasis models to detect the function of MLLT10 in vivo, the results are same with the outcomes in vitro. In lung metastasis sites, the knockdown of MLLT10 in SW620 cells significantly inhibited Vimentin expression, whereas the E-Cadherin was increased. Conclusions: These results indicate that MLLT10 regulates the metastasis of CRC cells via EMT.

Targeting autophagy enhances apatinib-induced apoptosis via endoplasmic reticulum stress for human colorectal cancer

Apatinib, a novel tyrosine kinase inhibitor (TKI), has been confirmed for its efficacy and safety in the treatment of advanced gastric carcinoma and some other solid tumors. However, the direct functional mechanisms of tumor lethality mediated by apatinib have not yet been fully characterized, and the precise mechanisms of drug resistance are largely unknown. Here, in this study, we demonstrated that apatinib could induce both apoptosis and autophagy in human colorectal cancer (CRC) via a mechanism that involved endoplasmic reticulum (ER) stress. Moreover, activation of the IRE1α pathway from apatinib-induced ER stress is responsible for the induction of autophagy; however, blocking autophagy could enhance the apoptosis in apatinib-treated human CRC cell lines. Furthermore, the combination of apatinib with autophagy inhibitor chloroquine (CQ) tends to have the most significant anti-tumor effect of CRC both in vitro and in vivo. Overall, our data show that because apatinib treatment could induce ER stress-related apoptosis and protective autophagy in human CRC cell lines, targeting autophagy is a promising therapeutic strategy to relieve apatinib drug resistance in CRC.

LIFR promotes tumor angiogenesis by up-regulating IL-8 levels in colorectal cancer

Leukemia inhibitory factor receptor (LIFR) has been documented as a cancer promoter and to be present at high levels in various types of tumor tissues. In our search for molecules prognostic of colorectal cancer (CRC), we found high levels of LIFR in CRC tissue samples. Further analyses revealed that LIFR was indeed prognostic of CRC patient survival, and was associated with tumor size, lymphatic metastasis and stages. LIFR was found to promote tumor growth, metastasis and angiogenesis both in vitro and in vivo. High levels of LIFR in CRC facilitated proliferation and migration of endothelial cells, resulting in an increase in angiogenic activity. Moreover, interleukin 8 (IL-8) was found to play a role in the LIFR induced angiogenesis. IL-8 levels were correlated with LIFR levels in CRC tissues, whereas depletion of IL-8 led to a reduced angiogenic activity of LIFR in CRC cells. In addition, LIFR increased phosphorylation level of Erk, which regulates il-8 transcription. We conclude that LIFR is possibly a valuable prognostic marker for CRC. Our results also implicate a mechanism by which LIFR regulates tumor angiogenesis through Erk/IL-8 pathway, and that LIFR could be a potential therapeutic target for CRC.