DDB1 and CUL4 associated factor 13 (DCAF13) is a protein coding gene located on chromosome 8q22.3, which is a hotspot amplified in various cancers. DCAF13 has been reported to be frequently amplified in breast cancer patients. However, the genetic alteration and potential role of DCAF13 in other cancers, including hepatocellular carcinoma, have not been investigated yet. In this study, we found that DCAF13 was amplified in 14.7% of the cases and its expression was upregulated (p < 0.001) in hepatocellular carcinoma samples in The Cancer Genome Atlas dataset. Increased expression of DCAF13 was also noticed in 40 paired hepatocellular carcinoma and adjacent non-tumor tissues both at messenger RNA and protein levels (p = 0.0002 and 0.0016, respectively). A positive relationship was observed between augmented DCAF13 levels and poorer tumor grade (p = 0.005), and we also found that hepatocellular carcinoma patients with increased DCAF13 expression in their tumors had significantly poorer survival compared with those with decreased DCAF13 expression (median survival time: 45.73 and 70.53 months, respectively). Multivariate Cox regression analysis showed that DCAF13 was an independent prognostic predictor of survival in hepatocellular carcinoma patients. Gene ontology and Kyoto Encyclopedia of Genes and genomes analysis indicated the potential role of DCAF13 as a crucial cell cycle regulator. Collectively, our findings revealed that the overexpression of DCAF13 in hepatocellular carcinoma was significantly associated with poor survival and may participate in the regulation of cell cycle progression.

Mutant p53 (mutp53) proteins promote tumor invasion and metastasis in pancreatic ductal adenocarcinoma (PDAC). However, the mechanism underlying sustained activation of mutp53 oncogenic signaling is currently unclear. In this study, we report that NOP14 nucleolar protein (NOP14) expression is upregulated in PDAC tumors and metastatic tissue specimens. NOP14 overexpression promoted cell motility, whereas NOP14 inhibition decreased invasive capacity of PDAC cells. In vivo invasion assays conducted on established subcutaneously, orthotopically, and intravenously injected tumor mouse models also indicated NOP14 as a promoter of PDAC metastasis. Mechanistically, mutp53 was validated as a functional target of NOP14; NOP14 primed tumor invasion and metastasis by increasing the stability of mutp53 mRNA. The NOP14/mutp53 axis suppressed p21 expression at both the transcriptional and posttranscriptional levels via induction of miR-17-5p in PDAC cells. In vivo, high NOP14 expression in PDAC patient tumors correlated with local metastasis and lymph invasion. Overall, our findings define a novel mechanism for understanding the function of NOP14 in the metastatic cascade of PDAC. Targeting NOP14 allows for effective suppression of tumor invasion in a mutp53-dependent manner, implicating NOP14 inhibition as a potential approach for attenuating metastasis in p53-mutant tumors. Cancer Res; 77(10); 2661–73. ©2017 AACR.

Gemcitabine serves as a first‐line chemotherapy agent for advanced pancreatic cancer (PC). However, the molecular basis by which gemcitabine exerts its effects is not well‐established, and the targeted genetic pathways remain unclear. Pvt1 oncogene (non‐protein coding) (PVT1) has been reported to be an oncogenic long non‐coding RNA in tumorigenesis. In the present study, we show that the expression of PVT1 is correlated with gemcitabine efficacy in PC therapy. Inhibition of PVT1 led to decreased cell growth in PC cells treated with gemcitabine. We also demonstrate that gemcitabine treatment decreases PVT1 levels and increases its encoded miRNAs, such as the miR‐1207 pair (miR‐1207‐5p/3p). Overexpression of the miR‐1207 pair enhanced the chemosensitivity of cells to gemcitabine, whereas silencing of miR‐1207‐5p/3p to prevent its induction by gemcitabine treatment led to increased cell growth. Mechanistic studies revealed that miR‐1207‐5p and miR‐1207‐3p target the SRC proto‐oncogene (non‐receptor tyrosine kinase) and ras homolog family member A in PC cells, respectively. In particular, we observed that gemcitabine induced Drosha ribonuclease III (Drosha) and DGCR8 microprocessor complex subunit (DGCR8) upregulation and then triggered PVT1 processing. Suppression of Drosha and DGCR8 contributed to a dampened efficacy of gemcitabine, indicating that gemcitabine decreased PVT1 expression by promoting its processing into miRNAs, which in turn resulted in blunted oncogenic signaling in PC cells. Moreover, we demonstrate that gemcitabine chemoresistance was a result of decreased expression of Drosha and DGCR8 in AsPC‐1 cells and tumor cell‐engrafted models. Overall, our findings define a novel mechanism for understanding the efficacy of gemcitabine chemotherapy in PC.

MicroRNAs function as oncomiRs and tumor suppressors in diverse cancers. However, the utility of specific microRNAs in predicting the clinical benefit of chemotherapy has not been well-established. Here, we investigated the correlation between microRNA-21 expression and hepatic arterial infusion chemotherapy with 5-fluorouracil and pirarubicin (HAIC) for hepatocellular carcinoma (HCC). We found that HCC patients with low microRNA-21 levels in tumors tended to have a longer time to recurrence and disease-free survival. We demonstrated that microRNA-21 suppression in combination with 5-fluorouracil and pirarubicin treatment inhibited tumor growth in subcutaneous xenograft mice models. Mechanistically, the AP-1 and microRNA-21-mediated axis was verified to be a therapeutic target of cytotoxic drugs and deregulation of this axis led to an enhanced cell growth in HCC. Taken together, our findings demonstrate that microRNA-21 is a chemotherapy responsive microRNA and can serve as a prognostic biomarker for HCC patients undergoing HAIC. Targeting microRNA-21 enhances the effect of chemotherapeutic drugs, thereby suggesting that microRNA-21 suppression in combination with HAIC may be a novel approach for HCC treatment.

Prolonged activation of nuclear factor (NF)-кB signaling significantly contributes to the development of colorectal cancer (CRC). New therapeutic opportunities are emerging from targeting this distorted cell signaling transduction. Here, we discovered the critical role of RING finger 138 (RNF138) in CRC tumorigenesis through regulating the NF-кB signaling, which is independent of its Ubiquitin-E3 ligase activity involved in DNA damage response. RNF138^−/− mice were hyper-susceptible to the switch from colitis to aggressive malignancy, which coincided with sustained aberrant NF-кB signaling in the colonic cells. Furthermore, RNF138 suppresses the activation of NF-кB signaling pathway through preventing the translocation of NIK and IKK-Beta Binding Protein (NIBP) to the cytoplasm, which requires the ubiquitin interaction motif (UIM) domain. More importantly, we uncovered a significant correlation between poor prognosis and the downregulation of RNF138 associated with reinforced NF-кB signaling in clinical settings, raising the possibility of RNF138 dysregulation as an indicator for the therapeutic intervention targeting NF-кB signaling. Using the xenograft models built upon either RNF138-dificient CRC cells or the cells derived from the RNF138-dysregulated CRC patients, we demonstrated that the inhibition of NF-кB signaling effectively hampered tumor growth. Overall, our work defined the pathogenic role of aberrant NF-кB signaling due to RNF138 downregulation in the cascade events from the colitis switch to colonic neoplastic transformation and progression, and also highlights the possibility of targeting the NF-кB signaling in treating specific subtypes of CRC indicated by RNF138-ablation.