DUSP7 inhibits cervical cancer progression by inactivating the RAS pathway
Authors: Bai Huimin , Jiao Ruili , Li Weihua , Zhao Jing , Xiao Meizhu , Song Meiying , Jin Mulan , Deng Haiteng , Zhang Zhengyu 
Published: December 2020

Abstract
Objective

The present study was aimed to determine the differentially expressed proteins (DEPs) between paired samples of cervical cancer (CC) and paracancerous tissue by quantitative proteomics and to examine the effects of DUSP7 expression on tumorigenesis and progression of CC.
Materials and methods

Proteomic profiles of three paired samples of CC and paracancerous tissue were quantitatively analyzed to identify the DEPs. The gene functions of the DEPs were presented based on bioinformatics analysis in combining with bibliographical information. The expression of the DEPs was validated by IHC examination in the CC tissue arrays. The relationship between the DEPs expression and patients’ clinicopathological characteristics and prognosis were evaluated using the Spearman rank correlation test and Kaplan-Meier survival analysis respectively. The effects of the selected DEPs on CC progression were examined in SIHA (human CC cell line) cells.
Results

According to the TMT (Tandem Mass Tags) ratios (≥ 1.5 or ≤ 0.5 ), a total of 129 proteins were found to be differentially expressed in all 3 pairs of samples with a p value < 0.05. To investigate gene functions of these DEPs in tumor growth and progresssion, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was performed. Three DEPs, HRAS, DUSP7, and PLD1, and P-ERK1/2, associated with RAS pathway, were selected for further investigation. Western Blot and IHC staining analyses confirmed the results from quantitative proteomic analysis showing that HRAS, P-ERK1/2, and PLD1 levels were increased whereas DUSP7 level was decreased in CC tissue compared with the paired normal paracancerous tissues. The IHC results from the CC TMA analysis showed that the decreased expression of DUSP7 (P = 0.045 and 0.044, respectively) and increased expression of PLD1 (P = 0.046 and 0.028, respectively) were significantly associated with a tumor size > 2 cm and parametrial infiltration. In addition, the decreased expression of DUSP7 and increased expression of PLD1 and p-ERK1/2 were adversely related to patients’ relapse (P = 0.003, 0.040, and 0.001, respectively) and survival (P = 0.034, 0.001, and 0.006, respectively). The expression of HRAS and p-ERK1/2 was decreased in DUSP7-SIHA cells compared to NC-SIHA cells (P = 0.0003 and 0.0026, respectively). Biological functions in vitro, including invasion, migration, and proliferation, and tumor formation in vivo were decreased in the DUSP7-SIHA cells (all P < 0.05), yet increased in the siDUSP7-SIHA cells (all P < 0.05).
Conclusions

DUSP7 is decreased in cervical cancer tissues compared to normal tissues. Increasing or decreasing DUSP7 expression was found to significantly reduce or enhance the anchorage-independent growth of SIHA cells, respectively. The biological function of DUSP7 is possibly achieved through dephosphorylation of the ERK1/2 and inactivation of the RAS pathway. Up-regulating the expression of DUSP7 may be potential useful for the prevention or treatment of CC.