Over-expression of CDX2 alleviates breast cancer by up-regulating microRNA let-7b and inhibiting COL11A1 expression

Abstract

Background: microRNA Let-7 serves as a tumor suppressor by targeting various oncogenic pathways in cancer cells. However, the underlying mechanism of its involvement in breast cancer remains largely unknown. With our research, our endeavor is to explore the role of the CDX2/let-7b/COL11A1 axis in breast cancer cell activities. Methods: Tumor tissues and adjacent normal tissues were collected from 86 patients with breast cancer. Human breast cancer epithelial cell line MCF-7 was treated with over-expressed CDX2, let-7b mimic, shRNA against COL11A1 and their negative controls. The expression of CDX2, let-7b, and COL11A1 in the tissues and cells was determined by RT-qPCR. Interactions among CDX2, let-7b, and COL11A1 were detected by ChIP and dual-luciferase reporter assay, respectively. After different transfections, cell invasion, migration, and proliferation abilities were determined by Transwell and EdU assays. Lastly, tumor xenografts in nude mice were established and hematoxylin and eosin staining was performed to assess the tumor growth and lymph node metastasis. Results: CDX2 and let-7b were poorly expressed in breast cancer cells and tissues. CDX2 bound to let-7b and promoted the expression of let-7b, which contrarily inhibited the expression of COL11A1. Cancer cell proliferation, invasion, migration, and metastasis were stimulated when CDX2 and let-7b were depleted or COL11A1 was overexpressed. Xenograft tumors growth and metastasis were in accordance with the results of cellular experiments. Conclusion: In agreement with these observations, we could reach a conclusion that CDX2 could promote let-7b expression, which may exert an inhibitory effect on the proliferation, migration, and metastasis of breast cancer cells via repressing the expression of COL11A1, providing a novel therapeutic strategy for the treatment of metastatic breast cancer.

CENPL, ISG20L2, LSM4 and MRPL3 Are Four Novel Hub Genes Involved in Breast Cancer Development and Progression

“…First of all, 512 robust DEGs between breast tumor tissues and normal breast tissues were identi ed using RRA method. Among them, COL11A1, S100P, LEP and FGF2 are the most signi cant DEGs, which have been reported to be associated with the pathogenesis and development of breast cancer [38][39][40][41]. Functional annotation analysis revealed that the robust DEGs signi cantly enriched in many GO terms associated with proliferation and energy metabolism, such as extracellular matrix organization, extracellular structure organization, mitotic nuclear division, regulation of lipid metabolic process, and glycosaminoglycan binding, which were consistent with published data [42][43][44].…”

Collagen Type XI Alpha 1 (COL11A1): A Novel Biomarker and a Key Player in Cancer

“…Another study in a mouse model of pancreatic cancer suggests that COL11A1 can be activated by the Hedgehog signaling pathway [ 68 ]. In xenograft mouse models of breast cancer, COL11A1 expression is negatively regulated by transcription factor CDX2 and microRNA let-7b and the loss of COL11A1 expression by upregulating CDX2 let-7b suppressed metastasis [ 55 ]. Muscle, intestine and stomach expression 1 (Mist1), a transcriptional repressor can inhibit COL11A1 expression and reverse EMT in a pancreatic cancer mouse model [ 67 ].…”

Identification of genes and pathways related to breast cancer metastasis in an integrated cohort

“…Degradation of matrix proteins, such as collagen, may serve as a critical step in the tumour cell invasion of surrounding tissues 40 . Several studies have explored the relationship between COL11A1 and breast cancer cells 41,42 . COL10A1 and COL5A1 have also shown prognostic significance in breast cancer 43,44 .…”