Recent studies suggest that several types of tumors preferentially metabolize glucose through aerobic glycolysis, a phenomenon known as the Warburg effect. However, it remains largely unexplored whether metabolic reprogramming is involved in prostate cancer (PCa) progression. In this study, we found that histone methyltransferase enhancer of zeste homolog 2 (EZH2) dysregulated in PCa development regulated cellular growth and aerobic glycolysis through miR-181b/hexokinase 2 (HK2) axis. Aberrant expression profiles of coding RNA and microRNA were examined by two large, independent clinical prostate cancer data sets. The results indicated that EZH2 expression was elevated followed by PCa development. A set of glycometabolism-related genes were positively correlated with EZH2 expression such as HK2. The depletion of EZH2 in cell experiments inhibited PCa cell growth and aerobic glycolysis accompanying the upregulation of miR-181b. Western blot and luciferase reporter assays showed that miR-181b inversely modulated HK2 by directly targeting the binding site within 3′-untranslated regions. Moreover, decreased miR-181b expression largely abrogated the effect of sh-EZH2 on HK2 expression and HK2-induced glucose metabolism process. Immunohistochemistry (IHC) and in situ hybridisation (ISH) analysis further revealed a significant correlation in EZH2, miR-181b and HK2 expression in nude mouse tumor xenograft. Taken together, these findings provide the first evidence that EZH2/miR-181b/HK2 pathway plays a positive role in PCa development. Targeting this aberrantly activated pathway may provide a new therapeutic strategy against PCa.
DKC1, an X‑linked gene encoding dyskerin at Xq28, is a crucial component of the telomerase complex and is indispensable for normal telomere function and the post‑-transcriptional modification of precursor rRNA. It has been revealed to exert diverse biological functions and prognostic values in numerous types of cancers. Our present study was aimed at examining DKC1 expression in normal renal tissues and clear cell renal cell carcinoma (ccRCC) samples and the prognostic value of DKC1 in ccRCC. We examined DKC1 protein expression levels in tissue microarrays including 307 cases of ccRCC tissues and in 75 pairs of ccRCC and paracancerous tissues with immunohistochemistry. The percentage of DKC1 expression in ccRCC (61.3%) was markedly higher than that in paracancerous tissues (34.7%) (P=0.001). Positive DKC1 expression tends to significantly be associated with unfavorable clinicopathological characteristics such as tumor diameter >7 cm (P=0.002) and tumor‑node‑metastasis (TNM) stage III or IV (P<0.001). Multivariate COX analysis revealed that positive DKC1 expression was an independent unfavorable factor for prognosis of ccRCC patients [hazard ratio (HR)=1.932, 95% CI, 1.290‑2.893, P=0.001 for 5‑year overall survival; HR=1.778, 95% CI,1.150‑2.748, P=0.010 for disease‑free survival]. In the PROGgeneV2 platform, we also found that ccRCC patients with high DKC1 mRNA expression had a poorer prognosis than patients with low DKC1 expression in The Cancer Genome Atlas (TCGA). Furthermore, we found that knockdown of DKC1 inhibited proliferation, migration and invasion of ccRCC through regulation of the NF‑κB/MMP‑2 signaling pathway in vitro. We also demonstrated that DKC1 regulated ccRCC proliferation and the expression of NF‑κB‑p65 and MMP‑2 in vivo. In summary, the expression of DKC1 was upregulated in ccRCC, which was associated with unfavorable clinicopathological characteristics and DKC1 may act as an independent prognostic indicator of ccRCC patients.
Pin2/TRF1‑binding protein X1 (PinX1) functioned as a potent inhibitor of telomerase, which was also widely considered to be a sufficient tumor suppressor. Previous studies have demonstrated that PinX1 expression was reduced in several types of cancer and was associated with poor overall survival. However, little is known regarding the role of PinX1 in colorectal cancer (CRC). The present study investigated PinX1 expression via immunostaining of CRC tissue microarrays consisting of tumor and adjacent non‑cancerous tissues (ANCT) from 568 patients. PinX1 expression was significantly lower in CRC tissues than in ANCT. Decreased PinX1 expression was revealed to be associated with lymph node metastasis, distant metastasis and advanced Tumor‑Node‑Metastasis stage, as well as a poorer overall and disease‑free survival. Furthermore, Cox regression analysis determined that a decreased PinX1 expression was an independent prognostic marker for patients with CRC. In an in vitro assay, PinX1 markedly restricted CRC cell migration and invasion. Additionally, the present study revealed that PinX1 could hinder the activity of matrix metalloproteinase 2 (MMP2) through nuclear factor (NF)‑κB‑dependent transcription to further suppress the migration and invasion ability of CRC cells through western blot analysis and a gelatin zymography assay. In vivo studies verified that PinX1 could suppress CRC metastasis, as well as the expression of MMP2 and NF‑κB p65. These results suggested that PinX1 can serve as an independent prognostic factor for patients with CRC and that it may function as a tumor metastasis suppressor in the progression of CRC though negatively regulating the NF‑κB/MMP2 signaling pathway.
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