Zhenqiang Sun

Jak-STAT3 pathway triggers DICER1 for proteasomal degradation by ubiquitin ligase complex of CUL4ADCAF1 to promote colon cancer development

Chronic intestinal inflammation is closely associated with colon cancer development and STAT3 seems to take center stage in bridging chronic inflammation to colon cancer progress. Here, we discovered that DICER1 was significantly downregulated in response to IL-6 or LPS stimulation and identified a novel mechanism for DICER1 downregulation via proteasomal degradation by ubiquitin ligase complex of CUL4A(DCAF1) in colon cancer cells. Meanwhile, PI3K-AKT signaling pathway phosphorylated DICER1 and contributed to its proteasomal degradation. The regulation of DICER1 by CUL4A(DCAF1) affected cell growth and apoptosis which is controlled by IL-6 activated Jak-STAT3 pathway. Intervention of CUL4A(DCAF1) ubiquitin ligase complex led to fluctuation in expression levels of DICER1 and microRNAs, and thus affected tumor growth in a mouse xenograft model. A panel of microRNAs that were downregulated by IL-6 stimulation was rescued by siRNA-CUL4A, and their predicated functions are involved in regulation of cell proliferation, apoptosis and motility. Furthermore, clinical specimen analysis revealed that decreased DICER1 expression was negatively correlated with STAT3 activation and cancer progression in human colon cancers. DICER1 and p-STAT3 expression levels correlated with 5-year overall survival of colon cancer patients. Consequently, this study proposes that inflammation-induced Jak-STAT3 signaling leads to colon cancer development through proteasomal degradation of DICER1 by ubiquitin ligase complex of CUL4A(DCAF1), which suggests a novel therapeutic opportunity for colon cancer.

Downregulation of long non-coding RNA ANRIL suppresses lymphangiogenesis and lymphatic metastasis in colorectal cancer

This study aimed to investigate the effect of ANRIL on the lymphangiogenesis and lymphatic metastasis in colorectal cancer. Using RT-PCT and Northern blot, we detected ANRIL expression in tissues (cancer vs. normal) and cell lines (HCoEpic, SW480, HT29, LoVo and HCT116), finding that ANRIL was overexpressed in colorectal cancer. By statistical analysis, increased ANRIL was found to be in close association with TNM staging, Duke staging and lymphatic metastasis and poor prognosis. We down-regulated the high ANRIL expression in LoVo and HCT116 with lentivirus transfection, and found that the activity of cell mobility and invasion was remarkably reduced. And also we also identified that ANRIL down-regulation could suppress in-vitro tube formation HLECs invasion. In addition, we built a mouse model of colorectal cancer. In the mouse model, we recorded, after ANRIL downregulation, decreased tumor growth rates and tumor size and reduced lymphatic metastasis rate and frequency of transferred lymph nodes, LMVD and expressions of VEFG-C, VEGFR-3 and LYVE-1. Based on these findings, we concluded that increased ANRIL is promoter in the development of colorectal cancer. Through down-regulation of the overexpressed ANRIL, lymphangiogenesis may be suppressed and therefore lymphatic metastasis may be inhibited. On this ground, we suggest that ANRIL may be a therapeutic target for colorectal cancer.

Prognostic Value of Yes-Associated Protein 1 (YAP1) in Various Cancers: A Meta-Analysis

Background Yes-associated protein 1 (YAP1) is an effector of Hippo pathway, which is critical for regulating organ size, cell proliferation and tumor growth in mammals. Many previous studies have explored the relationship between YAP1 and various types of cancer. However, these studies were limited by the small samples size and the findings were inconsistent among them. Therefore, a meta-analysis was conducted to assess the association between YAP1 and malignancies. Methods A systematic literature search was conducted for eligible studies in the PubMed, Corchane Library, Web of Knowledge, EMBASE and CBM disc databases from inception to August 1st 2014. After heterogeneity analysis, pooled harzad ratio (HR) with 95% confidence interval (95%CI) using both fixed and random effect models were estimated in STATA 10.0. Meta regression analysis, subgroup analysis and sensitivity analysis were performed to explore the potential sources of heterogeneity and to evaluate the robustness of the result. Publication bias was assessed by Egger’s test and funnel plot. Results A total of 21 unique articles from 2009 to 2014, comprising 2983 patients, were analyzed in the meta-analysis. The association of YAP1 expression and overall survival time (OS) was evaluated in 20 studies including 2067 patients. Positive YAP1 showed poorer OS (HR = 1.826; 95% CI = 1.465–2.275; p <0.002). For evaluating disease-free survival time (DFS), 10 studies with 1139 patients were analyzed. Positive YAP1 indicated worse DFS (HR = 2.114; 95%CI = 1.406–3.179; p <0.001). Subgroup analysis showed that both positive nuclear YAP1 (HR = 1.390, 95% CI: 0.810–2.400, p = 0.729) and up-regulation overall YAP1 (HR = 2.237, 95% CI: 1.548–3.232, p <0.001) had poorer OS for patients with malignancies. Similarly, both positive nuclear YAP1 (HR = 3.733, 95% CI: 1.469–9.483, p = 0.001) and up-regulation overall YAP1 (HR = 1.481, 95% CI: 1.163–1.886, p = 0.554) showed worse DFS. The patients with urogenital system cancer had the poorest OS (HR = 2.133, 95% CI: 1.549–2.937, p = 0.020). The patients with alimentary system cancer had the most significant impact on DFS (HR = 1.879, 95% CI: 1.537–2.297, p <0.001). Conclusion Both overall and nuclear YAP1 overexpression are intimately associated with adverse OS and DFS in numerous cancers, suggesting that YAP1 may act as a potential therapeutic targets of these malignancies in the future.

MiR-590-3p promotes proliferation and metastasis of colorectal cancer via Hippo pathway

Studies reported that miR-590-3p was involved in human cancer progression. However, its roles of oncogene or anti-oncogene in malignancies still remain elusive. This study was aimed to investigate the effect of miR-590-3p on the cell proliferation and metastasis via Hippo pathway in colorectal cancer (CRC). In our study, miR-590-3p was demonstrated highly expressed in CRC tissues, compared with adjacent normal tissues (P<0.05). In addition, miR-590-3p was positively associated with TNM stage and distant metastasis. Survival analysis showed that high miR-590-3p was related with poor overall survival rate. Then, over-expressed miR-590-3p was demonstrated to promote proliferation, invasion and migration of colon caner cells. What’s more, MST1, LATS1 and SAV1 mRNA were showed lowly expressed and YAP1 expression in mRNA and protein levels were highly expressed in CRC tissues, compared with adjacent normal tissues (all P<0.05). miR-590-3p expression was negatively associated with LATS1 and SAV1 mRNA respectively and positively related with YAP1 mRNA in CRC tissues, meanwhile, there was no relationship between miR-590-3p and MST1 mRNA. Furthermore, over-expressing miR-590-3p inhibited expressions of LATS1 and SAV1, promoted YAP1 expression and didn’t effect MST1 expression in colon cancer cells. And luciferase assay showed that miR-590-3p over-expression inhibited the luciferase activity of LATS1 and SAV1 3’UTR, meanwhile it had no effect on the mutated form of these two plasmids. Taken together, these data suggest that highly-expressed miR-590-3p promotes biological effect of proliferation and metastasis via targeting Hippo pathway, and predicts worse clinical outcomes of CRC patients.

Dual roles of yes-associated protein (YAP) in colorectal cancer

Yes-associated protein (YAP) is a downstream effector molecule of a newly emerging tumour suppressor pathway called the Hippo pathway. YAP is a transcriptional co-activator and mis-expressed in various cancers, including colorectal cancer (CRC). Accumulating studies show that the high expression of nuclear YAP is linked with tumour progression and decreased survival. Nuclear YAP can interact with other transcription factors to promote cancer cell proliferation, apoptosis, metastasis and maintenance of stemness. Therefore, YAP has the potential to be a tumour biomarker or therapeutic target for CRC. However, recently, a number of studies have supported a contradictory role for YAP as a tumour suppressor, demonstrating inhibition of the tumorigenesis of CRC, involvement in promoting cell apoptosis, and inhibiting the maintenance of intestinal stem cells and inflammatory activity. In these studies, high expression of YAP was highly correlated with worse survival in CRC. In this review, we will comprehensively summarize and analyse these paradoxical reports, and discuss both the oncogenic and tumour suppressor functions of YAP in the differential status of CRC progression. Further investigation into the mechanisms responsible for the dual function of YAP will be of great value in the prevention, early diagnosis, and therapy of CRC.

Appendiceal mucinous cystadenoma intussuscepted into the cecum on a patient with rectal carcinoma: a case report.

Appendiceal mucinous cystadenoma intussusception is rare but is readily ruptured and may form pseudomyxoma peritonei [1–3]. This condition is difficult to diagnose preoperatively due to its similarity to appendicitis or to atypical symptoms. A computed tomography (CT) scan, radioscopy, or colonoscopy can differentiate appendiceal mucinous cystadenoma intussusception from a cecal polyp or mass [4, 5]. Misdiagnosis may lead to treatment with false-polypectomy colonoscopy, which can result in appendiceal perforation and mucinous cystadenoma rupture. Etiologies include anatomical variations of the appendix and pathological conditions [6]. Especially in patients with rectal cancer, pseudomyxoma peritonei is difficult to detect.