Recent experimental evidence support the model in which the simultaneous induction of BMI-1 and USP22 is critical during cancer progression. Whether this model may affect gastric cancer (GC) progression is worthy of additional study. In this study, we examined the significance of the USP22 and BMI-1 expression in GC (n = 219), non-cancerous mucosa (n = 37), and lymph node metastasis (n = 37). The protein expression level of USP22 and BMI-1 were concomitantly up-regulated from non-cancerous mucosa to primary carcinoma and from carcinomas to lymph node metastasis (P < 0.001). A statistical correlation was observed between USP22 and BMI-1 expression in GC tissues (n = 219, r = 0.634, P < 0.001) and in lymph node metastasis (n = 37, r = 0.689, P < 0.001). The incidence of positive expression was 57.08% for USP22, 49.32% for BMI-1, and 45.21% for USP22/BMI-1 in 219 GC tissues, respectively. Co-positive of USP22/BMI-1 was significantly correlated with gross features (x(2) = 14.256, P < 0.001), differentiation (x(2) = 5.872, P = 0.015), pT classification (x(2) = 18.486, P < 0.001), pN classification (x(2) = 9.604, P = 0.002), pM classification (x(2) = 32.766, P < 0.001), and AJCC stage (x(2) = 58.278, P < 0.001). Notably, high USP22/BMI-1 expression was significantly associated with shorter disease-specific survival (P < 0.001). By Cox regression analysis, co-positive of USP22/BMI-1 was found to be an independent prognostic factor (P = 0.002). Our results indicated the simultaneous activation of USP22 and BMI-1 may associate with GC progression and therapy failure.

Accumulating evidence suggested the participation of long noncoding RNAs (lncRNAs) in regulating various biological processes so as to affecting cancer progression. However, the functional role of most lncRNAs in colorectal carcer (CRC) is still largely covered. In the present study, we disclosed SNHG14 as a carcinogene in CRC development, as it was low-expressed in normal colon tissues but markedly upregulated in CRC cell lines. Besides, SNHG14 contributed to CRC cell proliferation, motility and EMT in vitro, and inhibition of it confined CRC tumor growth and liver metastasis in vivo. Next, the mechanistic investigations confirmed that SNHG14-promoted CRC progression was mediated by EPHA7, which was negatively regulated by SNHG14 in CRC via an EZH2-dependent way. Importantly, EZH2 was proved as a transcription factor of EPHA7 and functioned as a repressor in EPHA7 transcription by enhancing methylation on EPHA7 promoter. Meanwhile, SNHG14 increased EZH2 expression in CRC via stabilizing its mRNA by interacting with FUS, and via freeing its mRNA from miR-186-5p-induced silence. All in all, our observations demonstrated that SNHG14 serves as a facilitator in CRC through targeting EZH2-repressed EPHA7 by enhancing EZH2 via recruiting FUS and absorbing miR-186-5p, indicating a promising new road for CRC diagnosis and treatment.

Colorectal cancer (CRC) remains both common and fatal, and its successful treatment is greatly limited by the development of stem cell‐like characteristics (stemness) and chemoresistance. MiR‐30‐5p has been shown to function as a tumor suppressor by targeting the Wnt/β‐catenin signaling pathway, but its activity in CRC has never been assessed. We hypothesized that miR‐30‐5p exerts anti‐oncogenic effects in CRC by regulating the USP22/Wnt/β‐catenin signaling axis. In the present study, we demonstrate that tissues from CRC patients and human CRC cell lines show significantly decreased miR‐30‐5p family expression. After identifying the 3’UTR of USP22 as a potential binding site of miR‐30‐5p, we constructed a luciferase reporter containing the potential miR‐30‐5p binding site and measured the effects on USP22 expression. Western blot assays showed that miR‐30‐5p decreased USP22 protein expression in HEK293 and Caco2 CRC cells. To evaluate the effects of miR‐30‐5p on CRC cell stemness, we isolated CD133 + CRC cells (Caco2 and HCT15). We then determined that, while miR‐30‐5p is normally decreased in CD133 + CRC cells, miR‐30‐5p overexpression significantly reduces expression of stem cell markers CD133 and Sox2, sphere formation, and cell proliferation. Similarly, we found that miR‐30‐5p expression is normally reduced in 5‐fluorouracil (5‐FU) resistant CRC cells, whereas miR‐30‐5p overexpression in 5‐FU resistant cells reduces sphere formation and cell viability. Inhibition of miR‐30‐5p reversed the process. Finally, we determined that miR‐30‐5p attenuates the expression of Wnt/β‐catenin signaling target genes (Axin2 and MYC), Wnt luciferase activity, and β‐catenin protein levels in CRC stem cells.

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The erythropoietin-producing hepatocyte (Eph) family tyrosine kinases play important roles in tumorigenesis and cancer aggression. In this study, we investigated the role of EphB6 in oncogenic transformation of colorectal epithelial cells in vitro and in vivo. EphB6 is upregulated in human colorectal cancer (CRC) tissues as compared to normal tissues, and its overexpression promotes proliferation, migration and invasion by IMCE colorectal adenoma cells, in which one Apc allele is mutated. EphB6 overexpression together with Apc mutation leads to the development of colorectal tumors in vivo. Expression microarrays using mRNAs and lncRNAs isolated from EphB6-overexpresssing IMCE and control cells revealed a large number of dysregulated genes involved in cancer-related functions and pathways. The present study is the first to demonstrate that EphB6 overexpression together with Apc gene mutations may enhance proliferation, invasion and metastasis by colorectal epithelial cells. Microarray data and pathway analysis of differentially expressed genes provided insight into possible EphB6-regulated mechanisms promoting tumorigenesis and cancer progression. EphB6 overexpression may represent a novel, effective biomarker predictive of cell proliferation, invasion and metastasis patterns in CRC tumors.