SULF2 promotes tumorigenesis and inhibits apoptosis of cervical cancer cells through the ERK/AKT signaling pathway

Abstract

The objective of this study was to explore the role of the SULF2-mediated ERK/AKT signaling pathway in cervical cancer. SULF2 expression was detected in tumor tissues and tumor-adjacent normal tissues from cervical cancer patients. HeLa cells were divided into six groups: control group, NC group, SULF2 siRNA group, SULF2 group, SULF2 + LY294002 group, and SULF2 + U0125 group. In each group, HeLa cells received the corresponding treatment, followed by measurement of the cellular biological characteristics and expression of the ERK/AKT signaling pathway. We also confirmed the effect of SULF2 in vivo using a xenograft model in nude mice. SULF2 was upregulated in cervical cancer tissues, which was specifically associated with the clinical stage, histological differentiation, and lymphatic metastasis. Compared to the control group, the SULF2 siRNA group displayed decreased expression of SULF2, concomitant with reduced proliferation, migration, and invasion, but there was an increase in the apoptosis rate of HeLa cells, as well as downregulation of the p-Akt/Akt, p-ERK/ERK, and Bax/Bcl-2 ratios and cyclin D1. Additionally, tumor growth was significantly inhibited in the xenograft model of nude mice. The results in the SULF2 group were quite the opposite in which SULF2 facilitated the growth of cervical cancer cells, which was reversed by LY294002 or U0126. SULF2 is highly expressed in cervical cancer, and thus, downregulation of SULF2 can inhibit the ERK1/2 and AKT signaling pathways to suppress the proliferation, invasion, and migration of cervical cancer cells while facilitating apoptosis.

Single-Cell RNA Sequencing Reveals Multiple Pathways and the Tumor Microenvironment Could Lead to Chemotherapy Resistance in Cervical Cancer

“…We also found that the extracellular sulfatase, SULT2, was highly expressed in the cancer samples, which is consistent with the findings of other studies (40). Upregulation of SULF2 gene expression is associated with proliferation, invasion, and migration of cervical cancer cells by its regulation of the extracellular signal-related kinase (ERK)/AKT signaling pathway (41). The ECM is important in tumor genesis and progression and fibroblast-activating protein (FAP), which plays a crucial role in ECM production and remodeling genes and is highly upregulated in tumor fibroblast cells (42).…”

Comprehensive Analysis of Common Different Gene Expression Signatures in the Neutrophils of Sepsis

“…Many aspects of the immune and inflammatory pathways were also significantly changed in our study. First, four and five of the top five up-and downregulated genes, respectively, were involved in inflammation and immune response signaling (Table 2); these corresponded to several aspects, including NF-κB signaling-driven inflammation and immunoregulation (FKBP5) [36][37][38], inflammation (SORT1, SH2B3, PLEKHO1, and PTPN6) [39][40][41][42], immune response to differentiation of monocytes to macrophages (CST7) [43], and apoptosis (GADD45A, PRR5L, and SULF2) [44][45][46]. Second, pathway analysis indicated that half of the top ten significantly changed sepsis pathways were related to immune and inflammatory signaling (Figure 4).…”

SULF2 Is a Prognostic Biomarker and Correlated with Tumor Associated Macrophages in Gastric Cancer

“…Chrysin was reported to have the ability to inhibit GC cells invasion 15 . There is a study suggested that chrysin has the antiproliferative activity against HCC through the suppression of SULF2 45 .…”

“…In fact, promotion of tumor progression via the increased expression of SULF2 is established in several types of cancers, including hepatocellular carcinoma (HCC) 12 , non-small cell lung cancer (NSCLC) 13 , colorectal cancer 14 , cervical cancer 15 , breast cancer 16 , pancreatic ductal adenocarcinoma 17 , neuroblastoma 18 , and head and neck squamous cell carcinoma (HNSC) 19 . In HCC, SULF2 acts as an oncogenic protein by increasing Wnt3a and glypican-3 (GPC3) expression and activating the Wnt/βcatenin pathway, thus promoting growth of HCC cell lines and xenografts 20 .…”

“…Moreover, SULF2 expression increases VEGF-A release and activity in TME in colorectal cancer 21 . And SULF2 promotes tumorigenesis through the ERK/AKT signaling pathway in cervical cancer and colorectal cancer 14,15 . Besides, in breast cancer, SULF2 facilitated lymphangiogenesis by regulating VEGF-D and the AKT1-related signaling pathway was involved 16 .…”