NUBPL, a novel metastasis-related gene, promotes colorectal carcinoma cell motility by inducing epithelial-mesenchymal transition.

Nucleotide binding protein-like, NUBPL, is an assembly factor for human mitochondrial complex I, which is the biggest member of the mitochondrial respiratory chain. However, the relationship between NUBPL and carcinoma progression remains unknown. In this study, NUBPL was characterized for its role in colorectal cancer (CRC) and the underlying molecular mechanisms. Data (n = 197) from the Oncomine database revealed that mRNA levels of NUBPL were remarkably overexpressed in CRC tissues compared with normal tissues. In addition, immunohistochemical analysis of 75 pairs of CRC and non-tumor tissues showed that the expression level of NUBPL was significantly higher in CRC tissues, and its expression level was positively associated with lymph node metastasis (P = 0.028) and advanced staging (P = 0.030). Expression of NUBPL in metastatic lymph nodes of CRC patients was also detected by immunohistochemical staining and high expression levels of NUBPL were observed. Overexpression of NUBPL significantly promoted the migration and invasion ability of CRC cell lines SW480 and SW620, whereas knockdown of NUBPL lead to an opposite effect. Our further study found that NUBPL could induce epithelial-mesenchymal transition (EMT), characterized by downregulation of epithelial markers (E-cadherin) and upregulation of mesenchymal markers (N-cadherin and vimentin). Moreover, NUBPL was able to activate ERK, which is believed to promote EMT and tumor metastasis. Inhibition of ERK suppressed the NUBPL-induced changes in EMT and cell motility. These data showed that NUBPL plays a vital role in CRC migration and invasion by inducing EMT and activating ERK. It might be a novel therapeutic target for CRC.

Wang Y ，Wu N ，Sun D ，Sun H ，Tong D ，Liu D ，Pang B ，Li S ，Wei J ，Dai J ，Liu Y ，Bai J ，Geng J ，Fu S ，Jin Y ... -  《-》

SPP1, analyzed by bioinformatics methods, promotes the metastasis in colorectal cancer by activating EMT pathway.

Tumor metastasis is still a great challenge for the prognosis of colorectal cancer (CRC). Although secreted phosphoprotein 1 (SPP1) over-expression is confirmed to associate with invasion, metastasis of CRC, the underlying mechanism by which modulates the CRC metastasis is still not fully explained. GDS4382 was obtained from GEO database and differentially expressed genes (DEGs) were analyzed by bioinformatics methods 55 paired samples of CRC and adjacent non-cancerous tissues were collected to detect the expression of SPP1 by q-PCR and western blot. Functional analysis of siRNA-SPP1, including proliferation, apoptosis, colony formation, cell cycle, migration, was investigated in CRC cell lines and tumor xenografts were conducted in nude mice. Protein expression of E-cadherin and vimentin was detected by western blot. 1887 DEGs were analyzed and selected from GDS4382, of which, SPP1 and epithelial-mesenchymal-transition (EMT) showed a close association by bioinformatics analysis. The mRNA and protein expression of SPP1 were significantly higher in CRC tissues than that in adjacent non-cancerous tissues (P<0.05). Overexpression of SPP1 closely associated with tumor invasion, metastasis and low survival in CRC. Moreover, siRNA-SPP1 repressed proliferation, cell cycle, colony formation, migration and tumor growth in vivo and promoted cell apoptosis in CRC cell lines. In addition, Protein expression of E-cadherin was obviously up-regulated and Vimentin was down-regulated in CRC cells after siRNA-SPP1 (P<0.05). SPP1 expression was significantly up-regulated in CRC. And SPP1 promoted the metastasis of CRC by activating EMT, which could be a potentially therapeutic target for patients with CRC.

Xu C ，Sun L ，Jiang C ，Zhou H ，Gu L ，Liu Y ，Xu Q ... -  《-》

Heat shock protein 90 promotes epithelial to mesenchymal transition, invasion, and migration in colorectal cancer.

Epithelial to mesenchymal transition (EMT), invasion, and motility are essential steps in colorectal cancer (CRC) metastasis regulated by HIF-1α and NF-κB. Since HSP90 activates HIF-1α and NF-κB, we hypothesized that inhibition of HSP90 leads to inhibition of HIF-1α and NF-κB resulting in inhibition of EMT, invasion, and motility. Treatment of colorectal cancer cell lines HT-29 and HCT-116 with ganetespib at 50 nM for 24 h inhibited EMT (downregulated vimentin and upregulated E-cadherin), matrigel invasion, and spheroid migration. Ganetespib treatment or HSP90 knockdown downregulated molecular pathways associated with EMT, invasion, and motility. The overexpression of HIF-1α or NF-κB resulted in increased EMT, invasion, and motility in both cell lines and these effects were inhibited by ganetespib. Similar effects were observed in animal xenografts treated with ganetespib. Taken together, our data demonstrate for the first time that inhibition of HSP90 downregulates both HIF-1α and NF-κB leading to inhibition of EMT, motility, and invasiveness in colorectal cancer.

Nagaraju GP ，Long TE ，Park W ，Landry JC ，Taliaferro-Smith L ，Farris AB ，Diaz R ，El-Rayes BF ... -  《-》

Short hairpin RNA- mediated gene knockdown of FOXM1 inhibits the proliferation and metastasis of human colon cancer cells through reversal of epithelial-to-mesenchymal transformation.

Yang K ，Jiang L ，Hu Y ，Yu J ，Chen H ，Yao Y ，Zhu X ... -  《JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH》

GRHL2 inhibits colorectal cancer progression and metastasis via oppressing epithelial-mesenchymal transition.

Yang Z ，Wu D ，Chen Y ，Min Z ，Quan Y ... -  《-》