BHLHE41 Overexpression Alleviates the Malignant Behavior of Colon Cancer Cells Induced by Hypoxia via Modulating HIF-1α/EMT Pathway.

Objective: BHLHE41 has been shown to be a marker of tumorigenesis. Colon cancer (CC) is a common malignant tumor of colonic mucosa. This study mainly explored the mechanism of BHLHE41 in alleviating malignant behavior of hypoxia-induced CC cells. Methods: The levels of BHLHE41 in CC and normal cell lines were tested by Western blot and qRT-PCR. After, CC cells were subjected to hypoxia treatment and BHLHE41 overexpression transfection, and the BHLHE41 expression, the effect of BHLHE41 on CC cell viability, apoptosis, migration, and invasion and cell cycle were tested by qRT-PCR and relevant cell functional experiments. HIF-1α and epithelial-mesenchymal transition- (EMT-) related proteins were tested by Western blot. Moreover, CC tumor-bearing model was established in nude mice, and the effect of BHLHE41 on the tumor was evaluated by measuring the tumor volume and weight. Then, the expressions of BHLHE41 and EMT-related proteins were detected by immunohistochemistry and Western blot. Results: Western blot and qRT-PCR showed that BHLHE41 was lowly expressed in CC cells. BHLHE41 overexpression could inhibit the hypoxia-induced CC cell viability, migration, and invasion, induce apoptosis, and alter cell cycle. Besides, BHLHE41 overexpression could enhance the levels of E-cadherin but reduce the levels of HIF-1α, N-cadherin, vimentin, and MMP9 in hypoxia-induced CC cells. Moreover, BHLHE41 overexpression reduced tumor volume, weight, and EMT-related proteins levels in tumor tissues. Conclusions: BHLHE41 overexpression could mitigate the malignant behavior of hypoxia-induced CC via modulating the HIF-1α/EMT pathway.

WITHDRAWN: LncRNA USP1 Knockdown Weakens the Progression of Colorectal Cancer via Modulating UBAP2L-Smad7-TGF-ß Pathway

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Schizandrin A exhibits potent anticancer activity in colorectal cancer cells by inhibiting heat shock factor 1.

Heat shock factor 1 (HSF1) is a powerful multifaceted oncogenic modifier that plays a role in maintaining the protein balance of cancer cells under various stresses. In recent studies, there have been reports of increased expression of HSF1 in colorectal cancer (CRC) cells, and the depletion of the HSF1 gene knockdown has inhibited colon cancer growth both in vivo and in vitro. Therefore, HSF1 is a promising target for colon cancer treatment and chemoprevention. In the present study, we found that Schizandrin A (Sch A) significantly inhibited the growth of CRC cell lines by inducing cell cycle arrest, apoptosis and death. Through HSE luciferase reporter assay and quantitative PCR (qPCR), we identified Sch A as a novel HSF1 inhibitor. In addition, Sch A could effectively inhibit the induction of HSF1 target proteins such as heat-shock protein (HSP) 70 (HSP70) and HSP27, whether in heat shock or normal temperature culture. In the Surface Plasmon Resonance (SPR) experiment, Sch A showed moderate affinity with HSF1, further confirming that Sch A might be a direct HSF1 inhibitor. The molecular docking and molecular dynamic simulation results of HSF1/Sch A suggested that Sch A formed key hydrogen bond and hydrophobic interactions with HSF1, which may contribute to its potent HSF1 inhibition. These findings provide clues for the design of novel HSF1 inhibitors and drug candidates for colon cancer treatment.

[Relationship between E-CD and Snail expressions and tumor invasion, metastasis and prognosis in colorectal cancer].

OBJECTIVE: To study the E-CD and Snail expressions in colorectal cancer and their relationship with colorectal cancer invasion, metastasis and prognosis. METHODS: Immunohistochemical staining (EnVision) was used to detect the E-CD and Snail expressions in 30 normal colorectal mucosa, 30 colorectal adenoma and 142 colorectal cancer tissues. RESULTS: E-CD in the normal colorectal mucosa was strongly positive expressed (90.0%), significantly higher than that in colorectal adenomas (63.3%) and colorectal cancer tissues (41.5%). E-CD expression was significantly related to tumor differentiation, invasion depth, vascular invasion, lymph node metastasis and Dukes' stage (P < 0.05), but not to the patients' age, gender, tumor size and tumor histological type (P > 0.05). The 1-, 3- and 5-year survival rates of the E-CD positive patients with colorectal cancer were significantly higher than that in E-CD negative patients. The positive expression rate of Snail in colorectal cancer tissues (52.1%) was significantly higher than that in normal colorectal mucosa (6.7%) and colorectal adenomas (26.7%, P < 0.05). The snail expression was significantly correlated to tumor histological type, differentiation, invasion depth, vascular invasion, lymph node metastasis and Duke's stage (P < 0.05), but not to patients' age, sex and tumor size (P > 0.05). The 1-, 3- and 5-year survival rates of Snail negative patients with colorectal cancer was significantly higher than that in patients with positive expression (P < 0.05). The expressions of E-CD and Snail in colorectal cancer tissues were inversely correlated (P < 0.05). Cox multivariate analysis showed that E-CD and Snail can be used as independent prognostic indicators (P < 0.05). CONCLUSION: E-CD and Snail expressions in colorectal cancer are related to the tumor invasion, metastasis and prognosis. Low expression of E-CD and high expression of Snail are related to the advanced stage, and poor prognosis in colorectal cancer patients. E-CD and Snail can be used as independent prognostic indicators.

[Clinical study of a new intracolonic drainage to protect low rectal anastomotic leakage].

OBJECTIVE: To investigate the value of using protective new intracolonic drainage in decreasing low colorectal anastomotic leakage. METHODS: One hundred and nineteen cases of rectal cancer accepted low anterior resection were randomly assigned to study group (n=55) and control group (n=64). The study group was added with a new intracolonic drainage composed of biofragmentable anastomosis ring and condom during operation. The control group was added with protective ileostomy during operation. The results of surgery were compared between the two groups. RESULTS: All the cases were followed up over three months and there were no perioperative death. There were no significant differences in physiopathological factors such as age, sex, body type, site of tumor, size of tumor, differentiation of tumor, site of anastomosis, condition of nutrition, concomitant disease between the two groups. In the study group, anastomotic leakage occurred in 4 cases (7.3%), the drainage devices were ablated 18.3 days after operations and there were no drainage-related complications; light anastomotic stenosis occurred in 3 cases (5.5%) three months after operations. Among the cases with leakage, no severe abdominal infection was found, the time of abdominal drainage was 4.8 days, and the amount of abdominal drainage was 12.8 ml/d in primary three days after leakage. In the control group, anastomotic leakage occurred in 7 cases (10.9%), ostomy-related complications occurred in 29 cases (45.3%), anastomotic stenosis occurred in 18 cases (28.1%) and severe anastomotic stenosis occurred in 4 cases (6.3%) after three months. Among the cases with leakage, severe infection occurred in two cases, anastomotic spoiled occurred in one case, the amount of abdominal drainage was 35.4 ml/d in primary three days after leakage, and the time of abdominal drainage was 17.1 days. There was no significant difference in the rate of anastomotic leakage between the two groups (P>0.05). But there were significant differences in the amount of abdominal drainage, the time of abdominal drainage and abdominal infection in the cases of anastomotic leakage (P<0.01). There was significant difference in anastomotic stenosis after three months between the two groups (P<0.01). CONCLUSIONS: The intracolonic drainage is a simple, safe and effective method in protecting low colorectal anastomotic leakage, and avoiding harmful results caused by anastomotic leakage. Compared with protective ileostomy, intracolonic drainage can avoid stomy-related physical mental suffering and complications, the rate of later anastomotic stenosis is less, and the time of abdominal drainage is shorter in the cases with leakage.

[Surgical treatment for local recurrence of rectal carcinoma after operation].

OBJECTIVE: To evaluate the value of reoperation for local recurrence of rectal carcinoma. METHODS: The data of 62 cases with post-operative local recurrence of rectal carcinoma were analyzed retrospectively. RESULTS: All the 62 patients received reoperation. Thirty two of those patients were treated with radical resection (16 patients combined multiple organ resection), 6 palliative resection, 11 colostomy, and 13 laparatomy only. The 1-, 3- and 5-year survival rates in the patients accepted radical resection were 90.6%, 59.4% and 18.8% respectively. But in patients undergone palliative resection and combined therapy, survival time was 6-24 months with median survival time of 16 months. The patients, accepted laparatomy and intra-abdominal chemotherapy, all died within 2-14 months postoperatively. For patients with postoperative recurrence time >5 years, <2 years and 2-5 years, the reoperation resection rates were 100%(11/11), 62.9%(22/35), and 31.3%(5/16) respectively, and there were significant differences among 3 groups (P<0.01). The rate of reoperation resection of pure local recurrence was 80.0%(32/40). The rate of reoperation resection of local recurrence, associated with near organ invasion, was 27.3%(6/22). The difference was significant(P<0.01). The reoperation resection rate of first operation with Dixon or Miles was 61.9%(26/42) and 30.0%(6/20), and the difference was significant as well(P<0.05). CONCLUSIONS: The recurrence of rectal carcinoma still needs positive operation in order to prolong the survival time and improve the quality of life of the patient. First operative procedure, post-operative recurrence time and recurrence type are important factors of reoperative resection.

[Rule of lymph node metastasis in colorectal cancer and its affecting factors].

OBJECTIVE: To investigate the rule of lymph node metastasis in colorectal cancer and its affecting factors, and to provide clues for clinical diagnosis and treatment of colorectal cancer patients. METHODS: The clinical data of 1166 cases of colorectal cancer receiving surgical resection were analyzed retrospectively.The relationships between clinicopathologic variables and lymph node metastases were evaluated by crosstabs and logistic regression in SPSS 10.0 for windows. RESULTS: The rate of lymph node metastasis in colorectal cancer was 49.7%. After entering crosstabs estimation, gender and tumor site were not significantly correlated with lymph node metastasis in colorectal cancer(chi2=1.46, r=0.035, P>0.05 and chi2=3.86, r=0.012, P>0.05). Age, tumor size, the massive type of the tumor, the differentiating degree of the tumor, histology type and the depth of tumor invasion were proved to be independent factors influencing the lymph node metastasis in colorectal cancer (chi2 =13.1, r=0.064, P<0.05 and chi2=77.161, r=0.245, P<0.01 and chi2=144.831, r=0.341, P<0.01 and chi2=128.310, r=0.318, P<0.01 and chi2=120.418, r=0.319, P<0.01 and chi2=227.287, r=0.434, P<0.01). After entering logistic regression estimation, the correlativity of risk factor of lymph node metastasis in colorectal cancer: the depth of tumor invasion > the massive type of the tumor>the differentiating degree of the tumor > tumor size. Preoperative blood serum CEA level was significantly correlated with lymph node metastasis (chi2=509.599, r=0.661, P<0.01). CONCLUSION: The depth of tumor invasion is the most risk factor of lymph node metastasis in colorectal cancer. Preoperative high level of blood serum CEA indicates the occurrence of lymph node metastasis.

[Study of prophylactic intra-iliac and hepatic arterial infusion chemotherapy against pelvic recurrence and liver metastasis after radical resection for rectal cancer].

OBJECTIVE: To study the effects of prophylactic intra-iliac and hepatic arterial infusion chemotherapy on pelvic recurrence and liver metastasis after radical resection for rectal cancer. METHODS: Eighty-four rectal cancer patients,undergone radical resection on Dukes stage B or C,were randomly assigned to postoperative intra-iliac and hepatic arterial infusion chemotherapy group(group I) and routine vein chemotherapy group(group II). Five-year survival and recurrence rates were compared between the two groups. RESULTS: Among the 84 rectal cancer patients with radical resection, the 5-year liver metastasis and pelvic recurrence rates were 30.2% (13/43) and 18.6% (8/43) respectively in group II, 17.1% (7/41) and 9.8% (4/41) in group I, the difference was significant between 2 groups (chi(2)=4.31, P<0.05). The mean tumor-free survival time was 26.2 months in group I and 15.8 months in group II (t=5.05, P<0.01), the difference was significant (t=5.05, P<0.01). The five-year survival rate in group I (65.9%) was significantly higher than that in group II (56.5%) (u=8.86, P<0.01). Cox multivariate analysis showed that, compared with those in group II, the relative risks of pelvic recurrence and liver metastasis in group I decreased 20% (coefficient of relative risk: 0.7959), and the five-year mortality also decreased 20% (coefficient of relative risk: 0.8034). CONCLUSION: Prophylactic intra-iliac and hepatic arterial infusion chemotherapy can reduce the rates of pelvic recurrence and liver metastasis after radical resection of rectal cancer.

[Statistical analysis of clinicopathologic characteristics of 1075 cases with colonic cancer].

OBJECTIVE: To investigate the clinicopathologic characteristics of colonic cancer. METHODS: All clinical data of surgical cases from hospital registry from 1982 to 2002 were analyzed using SPSS 11.0 software. RESULTS: There were 1075 patients with colonic cancer including 573 males and 502 females. The median age of the patients was 58 years. 90.8% of the patients aged over 40 years . The proportion of right colonic cancer was 64.7%. Well-differentiated and moderately differentiated adenocarcinoma accounted for 69.8%, and mucous carcinoma 13.6%. The proportions of early stage I, advanced stage II, III and IV cancer were 8.1%, 45.0%, 26.5% and 20.3% respectively. The 5-, 10-year survival rates were 61.9% and 53.0% respectively. CONCLUSIONS: The risk for colonic cancer is significantly increased in patients over 40 years. The frequency of right colonic cancer is higher than that of left colonic cancer. The overall survival rate is high.