CrkL regulates SDF-1-induced breast cancer biology through balancing Erk1/2 and PI3K/Akt pathways

Abstract

The adapter protein CrkL is required for regulating the malignant potential of human cancers. However, the regulatory mechanisms of CrkL on the stromal cell-derived factor 1 (SDF-1)/CXCR4 signaling pathways in breast cancer are not well characterized. Here, CXCR4 and CrkL proteins were tested in breast cancer cell lines and 60 primary breast cancer tissues. In vitro, the roles of CrkL in SDF-1-induced MDA-MB-231 cell cycle, invasion and migration were investigated. In the present study, CXCR4 and CrkL were highly expressed in MCF-7, MDA-MB-231, MDA-MB-231HM MDA-MB-468 and tumor tissues (80 and 60 %, respectively) and closely correlated with lymph node metastasis. In vitro studies revealed that SDF-1 induced the activation of CrkL, Erk1/2, Akt and matrix metallopeptidase 9 (MMP9) in MDA-MB-231 cells. The si-CrkL treatment significantly down-regulated the phosphorylated Erk1/2 (p-Erk1/2) and MMP9, but up-regulated p-Akt, compared with control. Importantly, wound-healing and transwell invasion assays showed that si-CrkL significantly impaired the wound closure and inhibited the SDF-1-induced invasion; similarly, flow cytometry showed that si-CrkL affected cell cycle. In conclusion, these results suggest that CrkL plays a regulatory role in the SDF-1-induced Erk1/2 and PI3K/Akt pathways and further managed the invasion and migration of breast cancer cells. Thus, CrkL may be recommended as an interesting therapeutic target for breast cancer.

16p11.2 transcription factor MAZ is a dosage-sensitive regulator of genitourinary development

“…Although many of the patients harbor the standard breakpoints covering ∼600 kb, a genomic space occupied by over 25 known genes, the CNVs of some GU patients were smaller and therefore more informative. Collectively the only gene within the minimal linear region of maximum CNV overlap is MAZ transcription factor, described in the literature as a simple housekeeping gene (38,39) but whose expression is known to influence the expression of other transcription factors (42,54,55). In addition to being the only gene occupying the 16p11.2 GU minimal region, MAZ has an exceptionally high haploinsufficiency rating (pLI score) of 0.95 according to the ExAC database of ∼61,000 individual genomes, meaning that the observed allele frequency for MAZ loss-of-function mutations is very low compared with what would be expected if MAZ were not haploinsufficient.…”

CRKL overexpression promotes cell proliferation and inhibits apoptosis in endometrial carcinoma

“…Although previous studies have reported that multiple aberrantly expressed genes in endometrial carcinoma could contribute to the malignant behavior (15,21–24), novel markers that are able to identify tumor progression and predict the aggressive phenotype are still urgently required. Upregulation of CRKL expression has been implicated in several human cancers, including breast cancer, lung cancer and pancreatic cancer (15,16,25,26), where it leads to increased proliferation and invasion.…”

ABCG2 confers promotion in gastric cancer through modulating downstream CRKL in vitro combining with biostatistics mining

“…Accumulating evidence has verified CRKL as a promoting factor in multiple cancer progress. CRKL participates in regulating the Erk1/2 and PI3K/Akt pathways and induces promotion of cell invasion and migration in breast cancer cells [29]; over-expression of CRKL significantly increases cell proliferation and invasion in two pancreatic cancer cell lines (Capan-2 and Bxpc-3), which suggests a promoting function of CRKL in pancreatic cancer [30]. In our previous research, CRKL was identified up-regulated in multiple GC cell lines, including MKN-45, SGC-7901 and MKN-2 cells [15].…”