THBS2, a microRNA‑744‑5p target, modulates MMP9 expression through CUX1 in pancreatic neuroendocrine tumors

Abstract

The underlying molecular mechanisms of pancreatic neuroendocrine tumor (pNET) development have not yet been clearly identified. The present study revealed that thrombospondin 2 (THBS2) was downregulated in pNET tissues and cells. Forced expression of THBS2 inhibited the proliferation and migration of pNET cells in vitro. MicroRNA(miR)-744-5p was indicated to be a direct regulator of THBS2. Upregulation of miR-744-5p potentially caused THBS2 repression. Furthermore, THBS2 inhibited the production of matrix metalloproteinase (MMP) MMP9 through suppressing the transcriptional activity of CUT-like homeobox 1 (CUX1). CUX1 and MMP9 mediated the effect of THBS2 on pNET proliferation and migration, respectively. The results of the present study revealed a mechanistic role for THBS2 in pNET proliferation and migration, indicating that THBS2 was downregulated by miR-744-5p and further affected the CUX1/MMP9 cascade, which promoted the development of pNET.

CUX1, A Controversial Player in Tumor Development

“…The p110 CUX1 activates a transcriptional program that reinforces the spindle assembly checkpoint and delays mitosis until extranumerary centrosomes have clustered to two poles, thereby enabling bipolar mitosis and survival of tetraploid cells (53). CUX1 was reported to promote the aggressiveness of pancreatic neuroendocrine tumor partly through modulating MMP9 expression (79). In addition, CUX1 was enriched in tumor-associated macrophages (TAMs) and interacted with nuclear factor κB (NF-κB) p65 to attenuate the activation of NF-κB signaling, leading to a decrease in T-cell attraction and an increase in angiogenesis in pancreatic cancer (80).…”

THBS2 promotes cell migration and invasion in colorectal cancer via modulating Wnt/β‐catenin signaling pathway

“…THBS2 and the Wnt/β‐catenin signaling pathway are known to be closely related in various cancers 9 . THBS2, a microRNA‐744‐5p target, modulates MMP‐9 expression through CUX1 in pancreatic neuroendocrine tumors 10 . Silencing of THBS2 inhibits gastric cancer cell proliferation, migration, and invasion, while promoting apoptosis through the PI3k‐Akt signaling pathway 11 .…”

Chemotherapy‐Enriched THBS2‐Deficient Cancer Stem Cells Drive Hepatocarcinogenesis through Matrix Softness Induced Histone H3 Modifications

“…Data expressed as the mean ± SEM; * p < 0.05, ** p < 0.01, and *** p < 0.001 from Student's t-test. a number of microRNAs including miR-744-5p, [41] miR-1246, [42] miR-221-3p, [43] and miR-20a. [44] Of note, our group has previously reported CD133+ liver CSCs to preferentially express miR-1246 in HCC; [45] but whether miR-1246 targets THBS2 in HCC will need to be further explored.…”