SREBP1 promotes the invasion of colorectal cancer accompanied upregulation of MMP7 expression and NF-κB pathway activation

Abstract

Background Sterol-regulatory element binding protein 1 (SREBP1), an intracellular cholesterol sensor located in the endoplasmic reticulum, regulates the intracellular cholesterol by the Insig-Srebp-Scap pathway. Over-expression of SREBP1 can cause dyslipidemia. SREBP1 can regulate the metabolic pathway, and then promote the proliferation of tumor cells. However, there is no relevant research of metastasis and invasion in the field of colorectal cancer (CRC). Methods Expression of SREBP1 was manipulated in CRC cell lines with low and high level SREBP1 expression by transfectiong with plasmids containing the SREBP1 gene, or by shRNA. The effect of SREBP1 on cell migration was assayed. The expression of SREBP1, p65 and MMP7 were detected by western blot. Human umbilical vein endothelial cell was used for detection of angiogenesis by adding the culture supernatant from HT29 and SW620. The level of reactive oxygen species (ROS) was detected by Dihydroethidium (DHE) staining. NF-κB inhibitor SN50 was used to test the relationship of SREBP1, NF-κB pathway and MMP7. Results We found that the expression of SREBP1 in colon adenocarcinoma was significantly higher than that in noncancerous tissues, especially in the invasive tumor front including tumor budding. In vitro, SREBP1 over-expressed in colon cancer cell lines HT29 promoted angiogenesis in endothelial cells, increased ROS levels, phosphorylation of NF-κB-p65 and increases MMP7 expression. The effect of SREBP1 on expression of MMP7 was lost following treatment with the NF-κB inhibitor SN50. Conclusion Our results suggest that SREBP1 can promote the invasion and metastasis of CRC cells by means of promoting the expression of MMP7 related to phosphorylation of p65. Electronic supplementary material The online version of this article (10.1186/s12885-019-5904-x) contains supplementary material, which is available to authorized users.

SREBP1 silencing inhibits the proliferation and motility of human esophageal squamous carcinoma cells via the Wnt/β‑catenin signaling pathway

“…ESCC tumor tissue analysis showed that patients in the high SREBP1 expression group had significantly poorer differentiation, more lymphatic metastasis and higher Ki-67 expression levels compared with those in the low SREBP1 expression group. The present data suggested that SREBP1-overexpression may contribute to the development of ESCC, which is consistent with SREBP1-overexpression previously described in ovarian tumor (24,48), glioblastoma (25), prostate (27), colorectal (28) and breast cancer (50,51), and nasopharyngeal carcinoma (NPC) (48). In addition, a number of studies have reported that SREBP1 participates in the proliferation of multiple cancer types (24,26,35,49).…”

“…Furthermore, according to the significant relationship between SREBP1 expression levels and lymphatic metastasis shown in the present study, SREBP1 was identified as a promoting factor regulating VEGF-C formation and secretion. Recently, studies have suggested that SREBP1 can participate in the metastasis of multiple tumors (28,49,51). Wound healing and Transwell assays in the present study revealed that cell migration and invasion were either upregulated or downregulated in response to SREBP1-overexpression or knockdown in ESCC cells, respectively.…”

Disruption of Cancer Metabolic SREBP1/miR-142-5p Suppresses Epithelial–Mesenchymal Transition and Stemness in Esophageal Carcinoma

“…We showed that the expression of SREBP1 was associated with the tumorigenic properties where it was associated with the EMT makers. Our results were supported by previous studies where increased SREBP1 expression facilitated EMT in breast and colon cancer [26,35]. In addition, studies have reported that SREBP1 is involved in the proliferation of multiple cancers [22,24,34,37].…”

“…SREBP1 is a critical transcription factor that controls the expression of genes important for the uptake and synthesis of lipids, such as cholesterol, fatty acids, and phospholipids [32]. Accumulating evidence suggests that SREBP1 facilitates tumor progression, and the upregulation of SREBP1 has often been detected in many cancer types [22][23][24][25][26][27][33][34][35][36]. In this study, we first identified an increased SREBP1 expression in different ESCC cohorts, which was in an inverse relationship with tumor suppressor miR-142-5p.…”

The matrix metalloproteinase 7 (MMP7) links Hsp90 chaperone with acquired drug resistance and tumor metastasis

“…The MMPs, in addition to digesting the ECM was also reported to have additional cellular functions; thus, they appear to be critical regulators of specific cell signal pathways. 29,41,42 MMPs majorly implicated in tissue remodeling, 1 understand the cross-talk if any between MMP7 and Hsp90. We reported earlier that cancer cells that exhibit resistance to Hsp90 inhibition might become aggressive when challenged with Hsp90 inhibitors.…”