Kaichun Wu

MicroRNA dysregulation in gastric cancer: a new player enters the game

Gastric carcinogenesis is a multistep process involving genetic and epigenetic alteration of protein-coding proto-oncogenes and tumor-suppressor genes. Recent discoveries have shed new light on the involvement of a class of noncoding RNA known as microRNA (miRNA) in gastric cancer. A substantial number of miRNAs show differential expression in gastric cancer tissues. Genes coding for these miRNAs have been characterized as novel proto-oncogenes and tumor-suppressor genes based on findings that these miRNAs control malignant phenotypes of gastric cancer cells. In this connection, miRNA dysregulation promotes cell-cycle progression, confers resistance to apoptosis, and enhances invasiveness and metastasis. Moreover, certain polymorphisms in miRNA genes are associated with increased risks for atrophic gastritis and gastric cancer, whereas circulating levels of miRNAs may serve as biomarkers for early diagnosis. Several miRNAs have also been shown to correlate with gastric cancer progression, and thus may be used as prognostic markers. Elucidating the biological aspects of miRNA dysregulation may help us better understand the pathogenesis of gastric cancer and promote the development of miRNA-directed therapeutics against this deadly disease.

MicroRNA-7 functions as an anti-metastatic microRNA in gastric cancer by targeting insulin-like growth factor-1 receptor

Metastasis is a major clinical obstacle in the treatment of gastric cancer (GC) and it accounts for the majority of cancer-related mortality. MicroRNAs have recently emerged as regulators of metastasis by acting on multiple signaling pathways. In this study, we found that miR-7 is significantly downregulated in highly metastatic GC cell lines and metastatic tissues. Both gain-of-function and loss-of-function experiments showed that increased miR-7 expression significantly reduced GC cell migration and invasion, whereas decreased miR-7 expression dramatically enhanced cell migration and invasion. In vivo metastasis assays also demonstrated that overexpression of miR-7 markedly inhibited GC metastasis. Moreover, the insulin-like growth factor-1 receptor (IGF1R) oncogene, which is often mutated or amplified in human cancers and functions as an important regulator of cell growth and tumor invasion, was identified as a direct target of miR-7. Silencing of IGF1R using small interefering RNA (siRNA) recapitulated the anti-metastatic function of miR-7, whereas restoring the IGF1R expression attenuated the function of miR-7 in GC cells. Furthermore, we found that suppression of Snail by miR-7, through targeting IGF1R, increased E-cadherin expression and partially reversed the epithelial–mesenchymal transition (EMT). Finally, analyses of miR-7 and IGF1R levels in human primary GC with matched lymph node metastasis tissue arrays revealed that miR-7 is inversely correlated with IGF1R expression. The present study provides insight into the specific biological behavior of miR-7 in EMT and tumor metastasis. Targeting this novel miR-7/IGF1R/Snail axis would be helpful as a therapeutic approach to block GC metastasis.

Meta-analysis: pre-operative infliximab treatment and short-term post-operative complications in patients with ulcerative colitis

Aliment Pharmacol Theru200231, 486–492

Systematic review: faecal microbiota transplantation therapy for digestive and nondigestive disorders in adults and children

There has been growing interest in the use of faecal microbiota transplantation (FMT) for the treatment of gastrointestinal and nongastrointestinal diseases.

miR-508-5p regulates multidrug resistance of gastric cancer by targeting ABCB1 and ZNRD1.

Multidrug resistance (MDR) is usually correlated with the poor prognosis of gastric cancer. In this study, we revealed a total of 11 microRNAs (miRNA) that regulated MDR of gastric cancer via high-throughput functional screening, and miR-508-5p reversed MDR most efficiently among these candidate miRNAs. The overexpression of miR-508-5p was sufficient to reverse cancer cell resistance to multiple chemotherapeutics in vitro and sensitize tumours to chemotherapy in vivo. Further studies showed that miR-508-5p could directly target the 3′-untranslated regions of ABCB1 and Zinc ribbon domain-containing 1 (ZNRD1), and suppress their expression at the mRNA and protein levels. Meanwhile, the suppression of ZNRD1 led to a decrease in ABCB1. These findings suggest that a miR-508-5p/ZNRD1/ABCB1 regulatory loop has a critical role in MDR in gastric cancer. In addition, miR-508-5p could be used as a prognostic factor for overall survival in gastric cancer. These data reveal an important role for miR-508-5p in the regulation of MDR in gastric cancer, and suggest the potential application of miR-508-5p in drug resistance prediction and treatment.

Meta-analysis: effect of preoperative infliximab use on early postoperative complications in patients with ulcerative colitis undergoing abdominal surgery

Infliximab is widely used in severe and refractory ulcerative colitis (UC). The results of clinical studies are inconsistent on whether preoperative infliximab use increases early postoperative complications in UC patients.

MicroRNA-296-5p increases proliferation in gastric cancer through repression of Caudal-related homeobox 1.

Caudal-related homeobox 1 (CDX1), an intestinal-specific transcription factor, has been reported to have vital roles in gastric intestinal metaplasia (IM). Although IM is a high-risk factor for gastric cancer (GC), the specific role of CDX1 in GC is largely unknown. In this study, we investigated the expression of CDX1 and its functional roles in GC, and its upstream regulatory mechanisms at the microRNA (miRNA) level were further explored. We found that CDX1 is lost in GC when compared with adjacent IM tissues. Gain-of-function studies showed that CDX1 significantly inhibited GC cell growth by inducing cell cycle arrest and apoptosis. Interestingly, we identified and verified an onco-mir, miR-296-5p, as a direct upstream regulator of CDX1. miR-296-5p overexpression significantly promoted GC cell growth and attenuated the CDX1-induced anti-growth effects by recurring cell cycle distribution and apoptotic status, whereas knockdown of miR-296-5p decreased GC cell growth. Furthermore, we found that the extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation and the subsequent downstream changes in protein levels related to cell cycle and apoptosis partly account for the miR-296-5p–CDX1-induced GC growth promotion. In addition, the detection of miR-296-5p and expression of CDX1 in primary GC tissues and adjacent IM tissues revealed that miR-296-5p is inversely correlated with CDX1, further supporting our in vitro results. Our results showed an anti-growth effect of CDX1 and identified its miRNA regulatory mechanism in GC. The identification of this novel miR-296-5p–CDX1–ERK1/2 axis sheds new light on the understanding of the process from IM to GC and may provide therapeutic targets for the treatment of GC.

STIM1, a direct target of microRNA-185, promotes tumor metastasis and is associated with poor prognosis in colorectal cancer.

STIM1 (stromal interaction molecule 1), an endoplasmic reticulum Ca2+ sensor that triggers the store-operated Ca2+ entry activation, has recently been implicated in cancer progression. However, the role of STIM1 in the progression and metastasis of colorectal cancer (CRC) has not been addressed. In this study, we confirmed increased expression of STIM1 in highly invasive CRC cell lines. Enhanced expression of STIM1 promoted CRC cell metastasis in vitro and in vivo, whereas silencing of STIM1 with small interfering RNA resulted in reduced metastasis. Ectopic expression of STIM1 in CRC cells induced epithelial-to-mesenchymal transition (EMT), whereas silencing of STIM1 had the opposite effect. Furthermore, STIM1 expression was markedly higher in CRC tissues than in adjacent noncancerous tissues. STIM1 overexpression correlated with poor differentiation and higher tumor node metastasis stage. CRC patients with positive STIM1 expression had poorer prognoses than those with negative STIM1 expression. Moreover, STIM1 was found to be a direct target of miR-185, a microRNA (miRNA) that has not previously been reported to be involved in EMT, in both CRC tissues and cell lines. Taken together, these findings demonstrate for the first time that STIM1 promotes metastasis and is associated with cancer progression and poor prognosis in patients with CRC. In addition, we show that expression of STIM1 is regulated by a posttranscriptional regulatory mechanism mediated by a new EMT-related miRNA. This novel miR-185–STIM1 axis promotes CRC metastasis and may be a candidate biomarker for prognosis and a target for new therapies.

ACP5, a direct transcriptional target of FoxM1, promotes tumor metastasis and indicates poor prognosis in hepatocellular carcinoma.

Tartrate-resistant acid phosphatase 5 (ACP5), which is essential for bone resorption and osteoclast differentiation, promotes cell motility through the modulation of focal adhesion kinase phosphorylation. However, whether ACP5 contributes to the metastasis and progression of hepatocellular carcinoma (HCC) remains unknown. In this paper, a complementary DNA microarray, serial deletion, site-directed mutagenesis and a chromatin immunoprecipitation assays confirmed that ACP5 is a direct transcriptional target of Forkhead box M1 (FoxM1). ACP5 expression was markedly higher in HCC tissues compared with adjacent noncancerous tissues. ACP5 overexpression was correlated with microvascular invasion, poor differentiation and higher tumor-node-metastasis stage. HCC patients with positive ACP5 expression had poorer prognoses than those with negative ACP5 expression. A multivariate analysis revealed that ACP5 expression was an independent and significant risk factor for disease recurrence and reduced-patient survival following curative resection. Transwell assays and an orthotopic metastatic model showed that the upregulation of ACP5 promoted HCC invasion and lung metastasis, whereas ACP5 knockdown inhibited these processes. The knockdown of ACP5 significantly attenuated FoxM1-enhanced invasion and lung metastasis. Immunohistochemistry revealed that ACP5 expression was positively correlated with FoxM1 expression in human HCC tissues, and their coexpression was associated with poor prognoses. In summary, ACP5 is a direct transcriptional and functional target of FoxM1. This novel FoxM1/ACP5 signaling pathway promotes HCC metastasis and may be a candidate biomarker for prognosis and a target for new therapies.

The miR27b-CCNG1-P53-miR-508-5p axis regulates multidrug resistance of gastric cancer.

Multidrug resistance (MDR) correlates with treatment failure and poor prognosis among gastric cancer (GC) patients. In a previous study using high-throughput functional screening, we identified 11 microRNAs (miRNAs) that regulate MDR in GC and found that miR-508-5p reversed MDR by targeting ABCB1 and ZNRD1. However, the mechanism by which miR-508-5p was decreased in chemo-resistant GC cells was unclear. In this study, we found that ectopic miR-27b is sufficient to sensitize tumors to chemotherapy in vitro and in vivo. Moreover, miR-27b directly targets the 3′ untranslated regions (3′-UTRs) of CCNG1, a well-known negative regulator of P53 stability. Interestingly, miR-27b up-regulation leads to increased miR-508-5p expression, and this phenomenon is mediated by CCNG1 and P53. Further investigation indicated that miR-508-5p is directly regulated by P53. Thus, the miR-27b/CCNG1/P53/miR-508-5p axis plays important roles in GC-associated MDR. In addition, miR-27b and miR-508-5p expression was detected in GC tissues with different chemo-sensitivities, and we found that tissues in which miR-27b and miR-508-5p are up-regulated are more sensitive to chemotherapy. Together, these data suggest that the combination of miR-27b and miR-508-5p represents a potential marker of MDR. Restoring the miR-27b and miR-508-5p levels might contribute to MDR reversion in future clinical practice.