A Preliminary Study of Immediate Intraperitoneal Chemotherapy for Stage III Colorectal Cancer.

OBJECTIVES: Investigate the survival of patients with stage III colorectal cancer (CRC) treated with immediate postoperative intraperitoneal chemotherapy. METHODS: The clinical data of 195 patients with stage III CRC admitted to The First Affiliated Hospital of Wenzhou Medical University from June 2017 to June 2018 were retrospectively analyzed. The patients were divided into an observation group and a control group, both groups were treated with the routine laparoscopic radical operation, on the basis of which, the patients in the observation group were treated with intraperitoneal perfusion chemotherapy during the operation. The local recurrence, abdominal cavity metastasis, and liver metastasis were followed up, and the time of disease recurrence and total survival were recorded. RESULTS: The survival analysis showed that there was a significant difference in progression-free survival (χ 2 = 5.416, P = 0.020) and overall survival (χ 2 = 4.673, P = 0.031) between the observation group and the control group. CONCLUSIONS: During laparoscopic radical resection of CRC, the use of intraperitoneal chemotherapy with raltitrexed can achieve satisfactory results and improve the survival rate of patients with stage III CRC, perioperative use of raltitrexed has been shown to be beneficial in terms of overall survival and progression-free survival.

Mir-4746 inhibits the proliferation of colorectal cancer cells in vitro and in vivo by targeting CCND1.

Colorectal cancer (CRC) is a commonly seen malignant tumor manifesting itself in the digestive tract, but it remains unclear what is the molecular mechanism behind its occurrence and development, which can have a significant impact on the clinical diagnosis and treatment of CRC. According to some studies, microRNA (miRNA) plays an essential role in the occurrence and development of cancer. In spite of this, there are still many miRNAs that play an important role in the progression of CRC but have yet to be reported. In our research, it was found out that the expression of mir-4746 is significantly down-regulated in CRC tissues and cells, and that its expression level is closely associated with the tumor size and prognosis of clinical patients. As revealed by function and mechanism experiments, targeting CCND1 mRNA 3'-UTR, mir-4746 can promote the degradation of CCND1 mRNA, thus reducing the protein level of CCND1, leading to cell G0-G1 phase arrest, and ultimately inhibiting the proliferation of CRC cells. For the first time, our study reported the biological functions of mir-4746 and its preliminary mechanism of action, in addition to demonstrating that mir-4746 can be applied as both a potential prognostic marker and the therapeutic target for CRC.

Overexpression of SIRT4 inhibits the proliferation of gastric cancer cells through cell cycle arrest.

The sirtuins (SIRTs) are a family of nicotinamide-adenine dinucleotide (NAD)+-dependent protein deacetylases. SIRT4 is a mitochondrial NAD+-dependent adenosine diphsophate-ribosyltransferase. Recent studies demonstrated that SIRT4 can regulate glutamine metabolism and thus act as a tumor suppressor. However, the association of SIRT4 with gastric cancer remains unknown. The present study investigated the potential role of SIRT4 in the proliferation of human gastric cancer cells. Gastric cancer cell lines (SGC-7901 and MNK45) overexpressing SIRT4 were established by lentiviral infection. The effect of overexpression of SIRT4 in gastric cancer was evaluated by determining the cell viability, proliferation activity and colony-forming ability of gastric cancer cells in vitro. Furthermore, the cell cycle profiles of SGC-7901 and MNK45 cells overexpressing SIRT4 were evaluated to provide insights into potential underlying molecular mechanisms. Overexpression of SIRT4 significantly inhibited the proliferation and colony-forming ability of the gastric cancer cells in vitro. Furthermore, overexpression of SIRT4 induced G1 cell cycle arrest via suppression of phosphorylated extracellular signal-regulated kinase, cyclin D and cyclin E. In conclusion, the results of the present study indicated that SIRT4 may function as a tumor suppressor in gastric cancer by regulating cell proliferation, therefore SIRT4 may be a potential therapeutic target against this disease.

Macrophage migration inhibitory factor serves a pivotal role in the regulation of radiation-induced cardiac senescencethrough rebalancing the microRNA-34a/sirtuin 1 signaling pathway.

Radiotherapy significantly increases survival innumerous cancer patients, although it may have delayed adverse effects, including significant short­ and long­term effects on cardiovascular function, leading to significant morbidity and mortality. However, the mechanisms underlying these effects remain unclear. Cardiomyocyte senescence contributes to cardiovascular disease via impaired cardiac function. MicroRNA­34a (miR­34a) is a senescence­associated miR involved in the pathology of cardiovascular diseases, while macrophage migration inhibitory factor (MIF) is a cardioprotective cytokine with an important role in cardiovascular diseases. The present study aimed to determine whether MIF has a cytoprotective effect in cardiomyocytes exposed to radiation through modulating miR­34a. Human cardiomyocytes (HCMs) were incubated with MIF and then exposed to radiation. Cellular proliferation was measured using a Cell Counting Kit­8, while cellular senescence was evaluated based on the senescence­associated ß­galactosidase activity and the gene expression levels of cyclin­dependent kinase inhibitor 1a (Cdkn1a) and Cdkn2c. Oxidative stress was evaluated by measuring the generation of reactive oxygen species and malondialdehyde, as well as the expression of antioxidant genes. In addition, HCMs were treated with small interfering RNA against sirtuin 1 (SIRT1) to examine the role of this gene in MIF­associated rejuvenation following radiation­associated senescence. miR­34a was significantly increased in HCMs exposed to radiation, while MIF inhibited senescence by suppressing miR­34a. SIRT1 was identified as a target gene of miR­34a, mediating the anti­senescence effect induced by MIF. Furthermore, MIF rejuvenation involved rebalancing the oxidation process disturbed by radiation. These results provided direct evidence that inhibition of miR­34a by MIF protected against radiation­induced cardiomyocyte senescence via targeting SIRT1. Inhibition of miR­34a by MIF may thus be a novel strategy for combating cardiac radiation­associated damage.

The role of Reg IV in colorectal cancer, as a potential therapeutic target.

Regenerating islet-derived family, member 4 (Reg IV), a member of the Reg gene family, has been reported to be overexpressed in gastrointestinal tract cancers. Reg IV overexpression in tumor cells has been associated with carcinogenesis, tissue regeneration, proliferation and resistance to apoptosis. Reg IV activates the epidermal growth factor receptor (EGFR) signaling pathway in colon cancer and increases expression of B-cell lymphoma-2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xl), which are associated with the inhibition of apoptosis, results in mitogenic signaling in colon cancer cells, increase cell proliferation, metastasis and decreased apoptosis. Reg IV treatment inhibits 5-fluorouracil induced apoptosis, at least two mechanisms are involved in inhibition of apoptosis by Reg IV, including Bcl-2 and dihydropyrimidine dehydrogenase (DPD). These studies may lead to novel therapeutic strategies for cancers expressing Reg IV. Recently, one proteoglycan was confirmed to disrupt this signaling pathway to perform antitumor effect. This review summaries current knowledge of the expression and roles of Reg IV in human colorectal cancer, describes the possible signaling pathway which Reg IV activates, and discusses the relevance of Reg IV as a potential therapeutic target for cancer treatment.

Intake of cruciferous vegetables is associated with reduced risk of ovarian cancer: a meta-analysis.

BACKGROUND: Epidemiological studies on the association between cruciferous vegetable (CV) consumption and the risk of ovarian cancer have demonstrated inconsistent results. We conducted a meta-analysis on CV consumption and ovarian cancer risk. METHODS: The relevant studies were identified by searching the Medline (Pubmed), Embase and Web of Science databases. The references of related articles and reviews up to October 2013 were also screened. The pooled relative risks (RRs) with 95% confidence intervals (CIs) for the highest versus the lowest CV consumption levels were calculated using a random-effects model. The heterogeneity and publication bias were also evaluated. RESULTS: Eight studies (4 case-control studies and 4 cohort studies) were identified and included in this meta-analysis. When all studies were pooled together, there was a significantly inverse association between CV consumption and the risk of ovarian cancer (RR: 0.89; 95% CI: 0.81-0.99). No significant heterogeneity or publication bias was found. CONCLUSIONS: The findings from this study suggest that the consumption of CVs may reduce the risk of ovarian cancer. Further investigations are needed to confirm the clinical effect of CVs on ovarian cancer.

MicroRNA-320b promotes colorectal cancer proliferation and invasion by competing with its homologous microRNA-320a.

Colorectal cancer metastasis is believed to be associated with microRNA dysregulation. However, little is known as to how microRNAs regulate colorectal cancer proliferation, invasion and metastasis. In the present study, we compared the microRNA expression profiles between patients of colorectal cancer at diagnosis with and without liver metastasis. MicroRNA-320b was found to be among those up-regulated in the patient group with metastasis. We subsequently found that microRNA-320b, opposite of its homolog, microRNA-320a that differs by only a single nucleotide, functions in promoting colorectal cancer cell proliferation and invasion. Moreover, we found that overexpression of exogenous microRNA-320b can up-regulate the target genes of microRNA-320a including ß-catenin, Neuropilin-1 and Rac-1, which are all known to promote tumor proliferation, invasion and metastasis. These results suggest that microRNA-320b may function in competing with microRNA-320a. Thus, our study has proposed one novel mechanism for controlling colorectal cancer proliferation and invasion through homologous competition between microRNAs. This mechanism may be important for colorectal cancer metastasis.

Consumption of garlic and risk of colorectal cancer: an updated meta-analysis of prospective studies.

AIM: To conduct an updated meta-analysis of prospective studies addressing the association between garlic consumption and colorectal cancer. METHODS: Eligible cohort studies were identified by searching MEDLINE (PubMed) and screening the references of related articles published up to October 2013. Meta-analyses were conducted for colorectal cancer in relation to consumption of raw and cooked (RC) garlic and garlic supplements, separately. The summary relative risks (RR) with 95%CI were calculated using fixed-effects or random-effects model depending on the heterogeneity among studies. RESULTS: A total of 5 prospective cohort studies were identified. In contrast to the previous meta-analysis, no significant associations were found between consumption of RC garlic (RR: 1.06; 95%CI: 0.95-1.19) or garlic supplements (RR: 1.12; 95%CI: 0.96-1.31) and risk of colorectal cancer. A non-significant protective effect of garlic supplement intake against colorectal cancer was observed in females (RR: 0.84; 95%CI: 0.64-1.11), but the opposite was the case in males (RR: 1.24; 95%CI: 0.96-1.59). CONCLUSION: Consumption of RC garlic or garlic supplements is not significantly associated with reduced colorectal cancer risk.

Estrogen receptor-α36 is involved in pterostilbene-induced apoptosis and anti-proliferation in in vitro and in vivo breast cancer.

Pterostilbene (trans-3,5-dimethoxy-4'-hudroxystilbene) is an antioxidant primarily found in blueberries. It also inhibits breast cancer regardless of conventional estrogen receptor (ER-α66) status by inducing both caspase-dependent and caspase-independent apoptosis. However, the pterostilbene-induced apoptosis rate in ER-α66-negative breast cancer cells is much higher than that in ER-α66-positive breast cancer cells. ER-α36, a variant of ER-α66, is widely expressed in ER-α66-negative breast cancer, and its high expression mediates the resistance of ER-α66-positive breast cancer patients to tamoxifen therapy. The aim of the present study is to determine the relationship between the antiproliferation activity of pterostilbene and ER-α36 expression in breast cancer cells. Methyl-thiazolyl-tetrazolium (MTT) assay, apoptosis analysis, and an orthotropic xenograft mouse model were used to examine the effects of pterostilbene on breast cancer cells. The expressions of ER-α36 and caspase 3, the activation of ERK and Akt were also studied through RT-PCR, western blot analysis, and immunohistochemical (IHC) staining. ER-α36 knockdown was found to desensitize ER-α66-negative breast cancer cells to pterostilbene treatment both in vitro and in vivo, and high ER-α36 expression promotes pterostilbene-induced apoptosis in breast cancer cells. Western blot analysis data indicate that MAPK/ERK and PI3K/Akt signaling in breast cancer cells with high ER-α36 expression are mediated by ER-α36, and are inhibited by pterostilbene. These results suggest that ER-α36 is a therapeutic target in ER-α36-positive breast cancer, and pterostilbene is an inhibitor that targets ER-α36 in the personalized therapy against ER-α36-positive breast cancer.

Cytohesins/ARNO: the function in colorectal cancer cells.

Epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I) are critical regulators of cell differentiation, survival, proliferation, and migration in cancers. This study found that ARNO (cytohesin-2), an activator of the EGF and IGF-I pathways, was more highly expressed in colorectal cancer tissue than in benign adjacent colorectal tissue. When ARNO-siRNA or the chemical inhibitor SecinH3 blocked ARNO, the downstream of the EGF and IGF-I pathways decreased in colorectal cell lines HT29 and HCT116. This blocking also weakened cell proliferation, invasion, and migration in vitro. Furthermore, EGF receptor (EGFR)-dependent colorectal tumor xenografts in nude mouse exerted anti-proliferative and growth suppression effects by injecting secineH3. These data suggested that inhibiting cytohesins or ARNO as cytoplasmic activators of EGFR and IGF-I in colorectal cancer resulted in anti-proliferation, reduced invasion, decreased migration, and suppressed growth in vivo and in vitro. Therefore, cytohesins or ARNO may be a potential therapy target for some colorectal cancer.

Function and mode of action of cytohesins in the epidermal growth factor pathway in colorectal cancer cells.

Cytohesins have been identified as cytoplasmic ErbB receptor activators in certain cancers, exhibiting an important role in ErbB signaling. However, whether cytohesins are essential in colorectal cancer is unknown. The aim of the present study was to investigate whether cytohesins contribute to the epidermal growth factor (EGF) pathway in colorectal cancer cells. RT-PCR and immunofluorescence experiments were employed to detect the expression of cytohesins in colorectal cancer cell lines. The EGF pathway activation conditions were investigated by examining the phosphorylation of the epidermal growth factor receptor (EGFR) and intracellular signal-related kinases, with or without chemical inhibition (SecinH3) and knockdown of cytohesins. An MTT assay was conducted to examine the inhibitory effect of SecinH3 and cytohesin-specific siRNA in HT-29 cells. Results demonstrated that the four homologous members of the cytohesin family were expressed in the four colorectal cancer cell lines. Notably, a significantly higher expression level of cytohesin-2 (ARNO) compared with the other three homologous family members was observed. Stimulation with EGF and SecinH3, as well as knockdown of ARNO, are capable of reducing EGF pathway activation and proliferation of HT-29 cells. In conclusion, cytohesins play an essential role in the activation of the EGF pathway and may be a potential target in colorectal cancer therapy.