Conventional therapies for breast cancer brain metastases (BCBMs) have been largely ineffective because of chemoresistance and impermeability of the blood-brain barrier. A comprehensive understanding of the underlying mechanism that allows breast cancer cells to infiltrate the brain is necessary to circumvent treatment resistance of BCBMs. Here, we determined that expression of a long noncoding RNA (lncRNA) that we have named lncRNA associated with BCBM (Lnc-BM) is prognostic of the progression of brain metastasis in breast cancer patients. In preclinical murine models, elevated Lnc-BM expression drove BCBM, while depletion of Lnc-BM with nanoparticle-encapsulated siRNAs effectively treated BCBM. Lnc-BM increased JAK2 kinase activity to mediate oncostatin M– and IL-6–triggered STAT3 phosphorylation. In breast cancer cells, Lnc-BM promoted STAT3-dependent expression of ICAM1 and CCL2, which mediated vascular co-option and recruitment of macrophages in the brain, respectively. Recruited macrophages in turn produced oncostatin M and IL-6, thereby further activating the Lnc-BM/JAK2/STAT3 pathway and enhancing BCBM. Collectively, our results show that Lnc-BM and JAK2 promote BCBMs by mediating communication between breast cancer cells and the brain microenvironment. Moreover, these results suggest targeting Lnc-BM as a potential strategy for fighting this difficult disease.

Colorectal cancer has a common cause of morbidity and mortality. Therefore, it is urgent to detect reliable biomarkers to predict prognosis in CRC. Here, we determined the expression of TIMP-2 and MMP-9 in a CRC tissue microarray by immunohistochemistry. We found that lower TIMP-2 or/and higher MMP-9 expression in cancer tissues was correlated with poorer overall survival (OS). TIMP-2 or MMP-9 expression was independent prognostic factors for CRC. Furthermore, TIMP-2 and MMP-9 expression had a synergistic role as efficient prognostic indicators for CRC patients. In vitro and in vivo, TIMP-2 could inhibit HCT 116 cells invasion and migration by regulating MMP-9. In sum, a combined expression of TIMP-2 and MMP-9 as efficient prognostic indicators was found for the first time.

Colorectal cancer (CRC) is one of the most common malignant tumors, and its high rates of recurrence and metastasis are the important causes of treatment failure in CRC. Therefore, the development of valuable molecular markers to accurately predict the prognosis of CRC patients is vital. In the present study, we determined the expression of Cullin1 (Cul1) and c-Myc in a CRC tissue microarray containing 470 cancer and corresponding normal tissues by immunohistochemistry. We found that Cul1 and c-Myc expression was significantly upregulated in the CRC cancer tissues compared with that noted in the adjacent non-cancer tissues. High Cul1 expression in cancer tissues was associated with depth of invasion (P=0.005), lymph node metastasis (P=0.001) and TNM stage (P=0.015). High c-Myc expression in cancer tissues was significantly positively association with age (P=0.004), depth of invasion (P<0.001), lymph node metastasis (P<0.001) and TNM stage (P<0.001). Multivariate Cox regression analysis revealed that Cul1 or c-Myc expression was an independent and unfavorable prognostic factor for CRC patients [hazard ratio (HR), 0.749, 95% confidence interval (CI), 0.563-0.996, P<0.05; and HR, 0.384, 95% CI, 0.257-0.472, P<0.001, respectively]. Furthermore, Cul1 and c-Myc exhibited synergistic potential for the prediction of CRC prognosis, and the patients with low expression of both Cul1 and c-Myc had a favorable survival outcome (P<0.001).

Protein/nucleic acid deglycase DJ‑1 (DJ‑1) is a 20‑kDa conserved protein, which belongs to the DJ‑1/ThiJ/Pfp Ⅰ protein superfamily. Immunohistochemistry was performed to investigate the expression of DJ‑1 in a colorectal cancer (CRC) tissue microarray containing tumor and corresponding adjacent normal tissues. In the present study, DJ‑1 expression was significantly upregulated in CRC cells and tissues, compared with that in normal colon cells and adjacent normal tissues, respectively. In addition, patients with high DJ‑1 expression levels had a worse overall survival (OS) compared with patients with low expression levels. Multivariate Cox regression analysis revealed that high DJ‑1 expression levels was an independent prognostic factor for patients with CRC. Moreover, DJ‑1 was able to regulate the PI3K/Akt/p27/cyclin E and PI3K/Akt/mTOR signaling pathways to promote CRC cell growth and metastasis in vitro and in vivo. In addition, DJ‑1 regulated the NF‑κB/Snail signaling pathway to induce CRC cell epithelial‑mesenchymal transition to promote migration and invasion. Notably, patients receiving LFP treatment (oxaliplatin, 5‑FU and tetrahydrofolate) had an increased OS compared with patients who underwent only surgery and low DJ‑1 expression levels. The findings from the present study suggest that DJ‑1 may serve as a promising prognostic marker and predicts chemotherapy efficacy in patients with CRC.

BACKGROUND: Cullin1 and MMP-2 have been identified as important markers in various cancers, but their roles in colorectal cancer (CRC) have remained to be discovered. The aim of this study was to investigate the expression pattern and significance of