Increased Thioredoxin-1 Expression Promotes Cancer Progression and Predicts Poor Prognosis in Patients with Gastric Cancer.

BACKGROUND: Thioredoxin-1 (Trx-1) is a small redox protein, which plays an important role in many biological processes. Although increased expression of Trx-1 in various solid tumors has been reported, the prognostic significance and function of Trx-1 in human gastric cancer (GC) are still unclear. Here, we investigated the clinical and prognostic significance of Trx-1 expression and the function and mechanism of Trx-1 in human GC. METHODS: We analyzed Trx-1 mRNA expression from the GEO database and Trx-1 protein expression in 144 GC tissues using immunohistochemistry. Effects of Trx-1 on GC cell were assessed in vitro and in vivo through Trx-1 knockdown or overexpression. The antitumor effects of the Trx-1 inhibitor, PX-12, on GC cells were investigated. PTEN and p-AKT expressions were evaluated by Western blotting. RESULTS: Increased Trx-1 expression was found in GC tissues and associated with poor prognosis and aggressive clinicopathological characteristics in patients with GC. High Trx-1 expression predicted poor prognosis, and its expression was an independent prognostic factor for overall survival of GC patients. Knockdown of Trx-1 expression inhibited GC cell growth, migration, and invasion in vitro and tumor growth and lung metastasis in vivo. Conversely, overexpression of Trx-1 promoted GC cell growth, migration, and invasion. We also found that PX-12 inhibited GC cell growth, migration, and invasion. Overexpression of Trx-1 caused a decrease in PTEN and increase in p-AKT levels whereas silencing Trx-1 caused an increase in PTEN and decrease in p-AKT levels in GC cells. Inhibition of AKT signaling pathway by MK2206 also inhibited GC cell growth, migration, and invasion. CONCLUSION: Our results indicate that Trx-1 may be a promising prognostic indicator and therapeutic target for GC patients.

HOXB8 enhances the proliferation and metastasis of colorectal cancer cells by promoting EMT via STAT3 activation.

BACKGROUND: Previous studies have demonstrated that the expression of homeobox8 (HOXB8) is higher in colorectal cancer (CRC) tissues than in normal tissues; however, the precise role of HOXB8 in human CRC cells remains to be elucidated. METHODS: We generated lentiviral constructs to overexpress and silence HOXB8 in CRC cell lines, and examined their biological functions through MTT, wound healing, colony and transwell, expression of signal transducer and activator of transcription 3 (STAT3) and epithelial-mesenchymal transition (EMT) related factors through western-blot. RESULTS: HOXB8 knockdown inhibited cellular proliferation and invasion in vitro as well as carcinogenesis and metastasis in vivo. HOXB8 also induced EMT, which is characterized by the down-regulation of E-cadherin and the up-regulation of Vimentin, N-cadherin, Twist, Zeb1 and Zeb2. Moreover, HOXB8 activated STAT3, which is known to play an oncogenic role in diverse human malignancies. CONCLUSIONS: Our results indicate that HOXB8 may be an independent prognostic factor in CRC. Therefore, deserved a deeper research.

Interplay between Trx-1 and S100P promotes colorectal cancer cell epithelial-mesenchymal transition by up-regulating S100A4 through AKT activation.

We previously reported a novel positive feedback loop between thioredoxin-1 (Trx-1) and S100P, which promotes the invasion and metastasis of colorectal cancer (CRC). However, the underlying molecular mechanisms remain poorly understood. In this study, we examined the roles of Trx-1 and S100P in CRC epithelial-to-mesenchymal transition (EMT) and their underlying mechanisms. We observed that knockdown of Trx-1 or S100P in SW620 cells inhibited EMT, whereas overexpression of Trx-1 or S100P in SW480 cells promoted EMT. Importantly, S100A4 and the phosphorylation of AKT were identified as potential downstream targets of Trx-1 and S100P in CRC cells. Silencing S100A4 or inhibition of AKT phosphorylation eliminated S100P- or Trx-1-mediated CRC cell EMT, migration and invasion. Moreover, inhibition of AKT activity reversed S100P- or Trx-1-induced S100A4 expression. The expression of S100A4 was higher in human CRC tissues compared with their normal counterpart tissues and was significantly correlated with lymph node metastasis and poor survival. The overexpression of S100A4 protein was also positively correlated with S100P or Trx-1 protein overexpression in our cohort of CRC tissues. In addition, overexpression of S100P reversed the Trx-1 knockdown-induced inhibition of S100A4 expression, EMT and migration and invasion in SW620 cells. The data suggest that interplay between Trx-1 and S100P promoted CRC EMT as well as migration and invasion by up-regulating S100A4 through AKT activation, thus providing further potential therapeutic targets for suppressing the EMT in metastatic CRC.

Thioredoxin-1 promotes colorectal cancer invasion and metastasis through crosstalk with S100P.

Thioredoxin-1 (Trx-1) is a small redox-regulating protein, which plays an important role in several cellular functions. Despite recent advances in understanding the biology of Trx-1, the role of Trx-1 and its underlying signaling mechanism in colorectal cancer (CRC) metastasis have not been extensively studied. In this study, we observed that Trx-1 expression is increased in CRC tissues compared to the paired non-cancerous tissues and is significantly correlated with clinical staging, lymph node metastasis and poor survival. Overexpression of Trx-1 enhanced CRC cell invasion and metastasis in vitro and in vivo. Conversely, suppression of Trx-1 expression decreased cell invasion and metastasis in vitro and in vivo. Moreover, Trx-1 activates S100P gene transcription. S100P, in turn, promotes Trx-1 expression and nuclear localization by upregulating p-ERK1/2 and downregulating TXNIP expression. Our finding provides new insight into the mechanism of Trx-1/S100P axis in the promotion of CRC metastasis, and suggests that the Trx-1/S100P axis and their related signaling pathways could be novel targets for the treatment of metastatic CRC.

miR-600 inhibits cell proliferation, migration and invasion by targeting p53 in mutant p53-expressing human colorectal cancer cell lines.

Mutations of the tumor protein p53 gene, a tumor suppressor, are one of the most frequent genetic alterations observed in cancer. It has been reported that mutations in p53 result in the loss of wild-type p53 activity, and the gain of novel oncogenic properties that promote tumor growth and progression. Recent studies have demonstrated that a number of microRNAs (miRs) are involved in the post-transcriptional regulation of p53. The present study demonstrates that miR-600 is a direct negative regulator of p53 through binding a site in the 3' untranslated region of p53 mRNA in human colorectal cancer (CRC) cells. Overexpression of miR-600 by lentiviral-mediated transduction decreased endogenous levels of p53 protein and inhibited cell proliferation, migration and invasion in mutant p53-expressing human CRC cell lines (SW480, SW620 and DLD-1) in vitro. In addition, silencing of p53 with small interfering RNA led to a similar phenotype. Furthermore, overexpression of miR-600 or p53 knockdown suppressed the expression of matrix metalloproteinase 9, and promoted the expression of E-cadherin and ß-catenin. The results of the current study demonstrate that miR-600 is an important negative regulator of p53, and suggest that targeting mutant p53 using lentiviral-mediated miR-600 overexpression is a promising therapeutic strategy for the treatment of CRCs with p53 mutations.

Identification of differentially expressed circular RNAs in human colorectal cancer.

Circular RNA, a class of non-coding RNA, is a new group of RNAs and is related to tumorigenesis. Circular RNAs are suggested to be ideal candidate biomarkers with potential diagnostic and therapeutic implications. However, little is known about their expression in human colorectal cancer. In our study, differentially expressed circular RNAs were detected using circular RNA array in paired tumor and adjacent non-tumorous tissues from six colorectal cancer patients. Expression levels of selected circular RNAs (hsa_circRNA_103809 and hsa_circRNA_104700) were measured by real-time polymerase chain reaction in 170 paired colorectal cancer samples for validation. Statistical analyses were conducted to investigate the association between hsa_circRNA_103809 and hsa_circRNA_104700 expression levels and respective patient clinicopathological features. Receiver operating characteristic curve was constructed to evaluate the diagnostic values. Our results indicated that there were 125 downregulated and 76 upregulated circular RNAs in colorectal cancer tissues compared with normal tissues. We also first demonstrated that the expression levels of hsa_circRNA_103809 ( p < 0.0001) and hsa_circRNA_104700 ( p = 0.0003) were significantly lower in colorectal cancer than in normal tissues. The expression level of hsa_circRNA_103809 was significantly correlated with lymph node metastasis ( p = 0.021) and tumor-node-metastasis stage ( p = 0.011), and the expression level of hsa_circRNA_104700 was significantly correlated with distal metastasis ( p = 0.036). The area under receiver operating characteristic curves of hsa_circRNA_103809 and hsa_circRNA_104700 were 0.699 ( p < 0.0001) and 0.616 ( p < 0.0001), respectively. In conclusion, these results suggest that hsa_circRNA_103809 and hsa_circRNA_104700 may be potentially involved in the development of colorectal cancer and serve as potential biomarkers for the diagnosis of colorectal cancer.