Activation of CXCL12/CXCR4 axis has been found to be associated with invasion and metastasis in many cancers. However, the underlying mechanism remains elusive. Increasing data highlight that non-coding RNAs are linked to CRC progression. The effects of CXCR4 were investigated using villin-CXCR4 transgenic mice model by flow cytometry assay, immunohistochemistry, and Western blot. The mechanism was explored through bioinformatics, luciferase reporter assay and RNA immunoprecipitation assay. We found that high CXCR4 expression exacerbated colitis-associated cancer in villin-CXCR4 transgenic mice. CXCR4+/−Apcmin/+ compound mutant mice demonstrated higher colorectal tumorigenesis than Apcmin/+ mice. Furthermore, overexpression of CXCR4 was found to promote the epithelial-mesenchymal transition (EMT) and infiltration of myeloid-derived suppressor cells (MDSCs) and macrophages in colonic tissue, accelerating colitis-associated and Apc mutation-driven colorectal tumorigenesis and progression. Notably, miR-133a-3p was found to be significantly decreased in HCT116 cells overexpressing CXCR4 by miRNA sequencing. miR-133a-3p was proved to target RhoA, which is involved in cytoskeletal reorganization that drive cell motility. Importantly, CXCL12/CXCR4-induced upregulation of lncRNA XIST functioned as a ceRNA to sponge miR-133a-3p, thereby liberating the repression of RhoA by miR-133a-3p. The negative correlation of miR-133a-3p with RhoA was also confirmed in human CRC tissues and CXCR4+/− mice. Our findings revealed the critical role of CXCR4 in promoting progression of inflammatory colorectal cancer through recruiting immunocytes and enhancing cytoskeletal remodeling by lncRNA XIST/ miR-133a-3p/ RhoA signaling. These results provide novel potential therapeutic targets for hindering CXCL12/CXCR4-induced CRC progression.

The activation of CXCL12/CXCR4 axis is associated with potential progression of cancer, such as invasion, metastasis and chemoresistance. However, the underlying mechanisms of CXCL12/CXCR4 axis and cancer progression have been poorly explored. We hypothesized that miRNAs might be critical downstream mediators of CXCL12/CXCR4 axis involved in cancer invasion and chemoresistance in CRC. In human CRC cells, we found that the activation of CXCL12/CXCR4 axis promoted epithelial-mesenchymal transition (EMT) and concurrent upregulation of miR-125b. Overexpression of miR-125b robustly triggered EMT and cancer invasion, which in turn enhanced the expression of CXCR4. Importantly, the reciprocal positive feedback loop between CXCR4 and miR-125b further activated the Wnt/β-catenin signaling by targeting Adenomatous polyposis coli (APC) gene. There was a negative correlation of the expression of miR-125b with APC mRNA in paired human colorectal tissue specimens. Further experiments indicated a role of miR-125b in conferring 5-fluorouracil (5-FU) resistance in CRC probably through increasing autophagy both in vitro and in vivo. MiR-125b functions as an important downstream mediator upon the activation of CXCL12/CXCR4 axis that involved in EMT, invasion and 5-FU resistance of CRC. These findings shed a new insight into the role of miR-125b and provide a potential therapeutic target in CRC.

Tamoxifen (TAM) and fulvestrant (FUL) are the major drugs for patients with estrogen receptor-positive (ER+) breast cancers. However, the development of endocrine resistance is the impediment for successful treatment. We aimed to explore the mechanisms of endocrine resistance and therapeutic strategy for overcoming resistance against TAM and FUL. Experiments were performed in ER+ and estrogen/TAM-sensitive MCF7 cells and antiestrogen-resistant MCF7/LCC9 cells. The expression of miR-214 and uncoupling protein 2 (UCP2) was determined by RT-qPCR and Western blot in breast cancer cells and human breast cancer tissue specimens. Cell autophagy was examined by fluorescent probe monodansyl cadaverine (MDC) and GFP-LC3-II-positive punctate identified by confocal microscopy. Apoptotic cells were determined by Annexin V-FITC/PI staining. The potential regulatory target of miR-214 was determined by prediction tool, target protein expression and luciferase reporter assay. 4-OHT/FUL treatment resulted in induction of apoptosis as well as autophagy in breast cancer cells. Autophagy might be the major cause of endocrine resistance to 4-OHT or FUL. MiR-214 increased the sensitivity of breast cancer cells to the 4-OHT/FUL-induced apoptosis through inhibition of autophagy. Importantly, a negative correlation was established between miR-214 and UCP2 in human breast cancer tissue specimens assayed by RT-qPCR. UCP2 was identified to be a direct target of miR-214. Further study in MCF7/LCC9 cells indicated that endocrine resistance might arise from activation of the PI3K-Akt-mTOR pathway, thereby inducing autophagy by overexpression of UCP2. MiR-214 increased the sensitivity of breast cancer cells to TAM and FUL through inhibition of autophagy by targeting UCP2. MiR-214 shows potential as a novel therapeutic strategy for overcoming endocrine resistance in ER+ breast cancers.

Invasion and metastasis of glioblastoma-initiating cells (GICs) are thought to be responsible for the progression and recurrence of glioblastoma multiforme (GBM). A safe drug that can be applied during the rest period of temozolomide (TMZ) maintenance cycles would greatly improve the prognosis of GBM patients by inhibiting GIC invasion. Resveratrol (RES) is a natural compound that exhibits anti-invasion properties in multiple tumor cell lines. The current study aimed to evaluate whether RES can inhibit GIC invasion in vitro and in vivo. GICs were identified using CD133 and Nestin immunofluorescence staining and tumorigenesis in non-obese diabetic severe combined immunodeficient (NOD/SCID) mice. Invasive behaviors, including the adhesion, invasion and migration of GICs, were determined by tumor invasive assays in vitro and in vivo. The activity of matrix metalloproteinases (MMPs) was measured by the gelatin zymography assay. Western blotting analysis and immunofluorescence staining were used to determine the expression of signaling effectors in GICs. We demonstrated that RES suppressed the adhesion, invasion and migration of GICs in vitro and in vivo. Moreover, we proved that RES inhibited the invasion of GICs via the inhibition of PI3K/Akt/NF-κB signal transduction and the subsequent suppression of MMP-2 expression.