Knockdown of RFC4 inhibits the cell proliferation of nasopharyngeal carcinoma <i>in vitro</i> and <i>in vivo</i>

doi:10.1007/s11684-022-0938-x

Front. Med.

2023, Vol. 17

Issue (1) : 132-142 https://doi.org/10.1007/s11684-022-0938-x

RESEARCH ARTICLE

Knockdown of RFC4 inhibits the cell proliferation of nasopharyngeal carcinoma in vitro and in vivo

Shuzhen Guan¹, Lin Feng², Jinrui Wei³, Guizhen Wang⁴(

), Lichuan Wu¹(

)

¹. Medical College of Guangxi University, Nanning 530004, China
². Department of Pathology, The First Medical Center of PLA General Hospital, Beijing 100853, China
³. Guangxi Scientific Research Center of Traditional Chinese Medicine, Guangxi University of Chinese Medicine, Nanning 530200, China
⁴. State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China

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Abstract

Nasopharyngeal carcinoma (NPC) is a malignant tumor that mainly occurs in East and Southeast Asia. Although patients benefit from the main NPC treatments (e.g., radiotherapy and concurrent chemotherapy), persistent and recurrent diseases still occur in some NPC patients. Therefore, investigating the pathogenesis of NPC is of great clinical significance. In the present study, replication factor c subunit 4 (RFC4) is a key potential target involved in NPC progression via bioinformatics analysis. Furthermore, the expression and mechanism of RFC4 in NPC were investigated in vitro and in vivo. Our results revealed that RFC4 was more elevated in NPC tumor tissues than in normal tissues. RFC4 knockdown induced G2/M cell cycle arrest and inhibited NPC cell proliferation in vitro and in vivo. Interestingly, HOXA10 was confirmed as a downstream target of RFC4, and the overexpression of HOXA10 attenuated the silencing of RFC4-induced cell proliferation, colony formation inhibition, and cell cycle arrest. For the first time, this study reveals that RFC4 is required for NPC cell proliferation and may play a pivotal role in NPC tumorigenesis.

Keywords nasopharyngeal carcinoma WGCNA RFC4 proliferation

Corresponding Author(s): Guizhen Wang,Lichuan Wu

Just Accepted Date: 28 October 2022 Online First Date: 22 December 2022 Issue Date: 15 March 2023

Cite this article:

Shuzhen Guan,Lin Feng,Jinrui Wei, et al. Knockdown of RFC4 inhibits the cell proliferation of nasopharyngeal carcinoma in vitro and in vivo[J]. Front. Med., 2023, 17(1): 132-142.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-022-0938-x
https://academic.hep.com.cn/fmd/EN/Y2023/V17/I1/132

Fig.1 RFC4 was identified as a potential key gene in NPC via bioinformatic analysis. (A–D) Network visualization of WGCNA analysis. (A) Sample dendrogram of 57 NPC tumor and normal samples. (B) Appropriate soft threshold power = 12 was selected. (C) Gene cluster tree. (D) Heatmap of the correlation between modules eigengenes and clinical traits. Numbers in the upper and round brackets of each rectangle show correlation and P value, respectively. Red represents positive correlation, whereas green indicates a negative correlation. (E) Identification of the largest and most dense cluster via PPI and MCODE analysis. (F) Expression of 7 genes in the inner circle of Cluster 1 was significantly correlated with patient survival. (G) Gene alteration analysis.

Fig.2 RFC4 was overexpressed in NPC. (A) Expression of RFC4 in NPC tumor and normal tissues via analyzing data from GEO data sets. (B) IHC results of RFC4 expression in normal and NPC tumors. *P < 0.05; **P < 0.01; ***P < 0.001.

Fig.3 RFC4 regulated NPC cell proliferation in vitro. (A) Growth curve of CNE2 and HK-1 cells transfected with siRFC4 or control siRNAs. (B) Colony formation of CNE2 and HK-1 cells transfected with siRFC4 or control siRNAs. (C) Cell cycle distribution after downregulating RFC4 in CNE2 and HK-1 cells. (D) Expression of CDK1 and CCNB1 was downregulated in CNE2 and HK-1 cells upon siRFC4 treatment. (E) Growth curve of HK-1 transfected with RFC4 overexpressing or control plasmids. (F) Colony formation of HK-1 cells transfected with RFC4 overexpressing or control plasmids. (G) Expression of CDK1 and CCNB1 was upregulated in HK-1 cells treated with RFC4 overexpressing plasmid. *P < 0.05; **P < 0.01; ***P < 0.001. ns, non-significance.

Fig.4 RFC4 regulated the expression of HOXA10 in NPC. (A) Volcano plot of DEGs. (B) Pathway enrichment analysis of 557 DEGs. (C) Expressions of 13 TFs. (D) Expression validation of 5 TFs in CNE2 and HK-1 cells via qPCR. (E) Correlation analysis between HOXA10/RELB and RFC4 via analyzing data from GEO and TCGA data sets. (F) HOXA10 was downregulated in CNE and HK-1 cells upon siRFC4 treatment. (G) HOXA10 was upregulated in HK-1 cells transfected with RFC4 overexpressing plasmid. *P < 0.05; **P < 0.01; ***P < 0.001. ns, non-significance.

Fig.5 Overexpressing of HOXA10 attenuated RFC4 silencing-induced inhibition of NPC cell proliferation. (A) Growth cure of CNE2 cells transfected with relative plasmids. (B) Colony formation of CNE2 cells transfected with relative plasmids. (C) Cell cycle distribution of CNE2 cells transfected with relative plasmids. (D) Expressions of CCNB1, CDK1, HOXA10, and RFC4 in CNE2 cells transfected with relative plasmids. *P < 0.05; **P < 0.01; ***P < 0.001.

Fig.6 Downregulation of RFC4 suppressed NPC tumor growth. (A) Image of tumor tissues after anatomy. (B) Curves of tumor volumes at various times. (C) Statistic of tumor weight. (D) Representative expression image of Ki67 in tumor tissues from each group. (E) The expressions of CCNB1, CDK1, HOXA10, and RFC4 in tumor tissues from each group. *P < 0.05; **P < 0.01; ***P < 0.001.

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