P4HA2通过激活EGFR/AKT/S6信号通路促进食管鳞癌细胞的增殖

doi:10.3969/j.issn.1004-616x.2023.02.002

Abstract

Abstract: OBJECTIVE： To investigate expression and implication of P4HA2 in esophageal squamous cell carcinoma (ESCC). METHODS： Expressions of P4HA2 mRNA in ESCC tissues and normal esophageal tissues were analyzed by Gene Expression Omnibus (GEO) database. P4HA2 protein in ESCC and normal tissues were detected using Immunohistochemistry (IHC) and Western blot. Cell proliferation and colony formation assays were performed to analyze effects of P4HA2 on the malignant phenotypes of ESCC cells in vitro. Effects of P4HA2 on tumor growth were detected using the nude mouse xenograft model in vivo. Western blot was used to analyze changes in downstream pathways from knockdown of P4HA2. RESULTS：Expression levels of both the P4HA2 mRNA and protein were up-regulated in ESCC compared with the normal tissues (P<0.01). In vitro and in vivo results showed that P4HA2 silencing significantly inhibited the proliferation and colony formation of ESCC cells，as well as the growth of tumor xenografts (P<0.01). At the molecular level， P4HA2 knockdown down-regulated EGFR expression，and reduced the phosphorylation levels of AKT and S6 (P<0.05). Moreover，P4HA2 knockdown and over-expression of EGFR significantly restored the phosphorylation levels of AKT and S6 as well as cell proliferation and colony formation (P<0.01). CONCLUSION：P4HA2 was highly expressed in ESCC，and it might enhance cell proliferation and promote development of ESCC via activating the EGFR/AKT/S6 pathway.

Key words: P4HA2, esophageal squamous cell carcinoma, cell proliferation, EGFR/AKT/S6 signaling pathway

CLC Number:

R735.1

FENG Dan, FAN Zhilu, WANG Yinong, LI Sai, GUO Jing, CAI Yan, ZHANG Yu, WEI Wenqiang, WANG Mingrong, HAO Jiajie. P4HA2 promotes proliferation of esophageal squamous carcinoma cells via activating the EGFR/AKT/S6 signaling pathway[J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2023, 35(2): 87-94,101.

References

[1] SUNG H，FERLAY J，SIEGEL R L，et al. Global cancer statistics 2020：GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin，2021，71(3)：209-249.
[2] AN L，ZHENG R S，ZENG H M，et al. The survival of esophageal cancer by subtype in China with comparison to the United States[J]. Int J Cancer，2023，152(2)：151-161.
[3] ANNUNEN P，HELAAKOSKI T，MYLLYHARJU J，et al. Cloning of the human prolyl 4-hydroxylase α subunit isoform α (II) and characterization of the type II enzyme tetramer[J]. J Biol Chem，1997，272(28)：17342-17348.
[4] CHANG K P，YU J S，CHIEN K Y，et al. Identification of PRDX4 and P4HA2 as metastasis-associated proteins in oral cavity squamous cell carcinoma by comparative tissue proteomics of microdissected specimens using iTRAQ technology[J]. J Proteome Res，2011，10(11)：4935-4947.
[5] ZHANG H B，ZHAO W. Prolyl-4-hydroxylase α subunit 2 as a novel potential biomarker for predicting the prognosis of epithelial ovarian carcinoma[J]. Cancer Manag Res，2021，13： 4455-4462.
[6] LI M J，WANG Q Y，ZHENG Q Q，et al. Prognostic and diagnostic roles of prolyl 4-hydroxylase subunit α members in breast cancer[J]. Biomark Med，2021，15(13)：1085-1095.
[7] LU X H，SANG D，ZHANG Y R，et al. High expression of prolyl 4-hydroxylase subunit alpha-2 in lung adenocarcinoma indicates poor prognosis[J]. Clinics (Sao Paulo)，2022，77： 100123.
[8] WU Y Y，ZHANG X R，WANG J，et al. P4HA2 promotes cell proliferation and migration in glioblastoma[J]. Oncol Lett，2021， 22(2)：601.
[9] CAO Y，HAN Q C，LI J，et al. P4HA2 contributes to cervical cancer progression via inducing epithelial-mesenchymal transition[J]. J Cancer，2020，11(10)：2788-2799.
[10] LI Q X，WANG Q Y，ZHANG Q Y，et al. Collagen prolyl 4-hydroxylase 2 predicts worse prognosis and promotes glycolysis in cervical cancer[J]. Am J Transl Res，2019，11(11)： 6938-6951.
[11] LI G B，JIANG W，KANG Y T，et al. High expression of collagen 1A2 promotes the proliferation and metastasis of esophageal cancer cells[J]. Ann Transl Med，2020，8(24)：1672.
[12] MA H P，CHANG H L，BAMODU O A，et al. Collagen 1A1(COL1A1) is a reliable biomarker and putative therapeutic target for hepatocellular carcinogenesis and metastasis[J]. Cancers，2019，11(6)：786.
[13] TU H B，LI J，LIN L，et al. COL11A1 was involved in cell proliferation，apoptosis and migration in non-small cell lung cancer cells[J]. J Invest Surg，2021，34(6)：664-669.
[14] RØMER A M A，THORSETH M L，MADSEN D H. Immune modulatory properties of collagen in cancer[J]. Front Immunol， 2021，12：791453.
[15] NOOROLYAI S，SHAJARI N，BAGHBANI E，et al. The relation between PI3K/AKT signalling pathway and cancer[J]. Gene，2019，698：120-128.
[16] SHANG L，JIANG W，ZHANG J，et al. P4HA2 promotes occurrence and progression of liver cancer by regulating the PI3K/Akt/mTOR signaling pathway[J]. J South Med Univ， 2022，42(5)：665-672.
[17] LIN J，JIANG L，WANG X G，et al. P4HA2 promotes epithelial-to-mesenchymal transition and glioma malignancy through the collagen-dependent PI3K/AKT pathway[J]. J Oncol，2021，2021：1406853.
[18] CAIRNS J，FRIDLEY B L，JENKINS G D，et al. Differential roles of ERRFI1 in EGFR and AKT pathway regulation affect cancer proliferation[J]. EMBO Rep，2018，19(3)：e44767.
[19] ELLIS L M. Epidermal growth factor receptor in tumor angiogenesis[J]. Hematol Oncol Clin North Am，2004，18(5)： 1007-1021.
[20] REN Y X，HONG Y L，HE W T，et al. EGF/EGFR promotes salivary adenoid cystic carcinoma cell malignant neural invasion via activation of PI3K/AKT and MEK/ERK signaling [J]. Curr Cancer Drug Targets，2022，22(7)：603-616.
[21] JANECKA-WIDŁA A，MAJCHRZYK K，MUCHA-MAŁECKA A，et al. EGFR/PI3K/Akt/mTOR pathway in head and neck squamous cell carcinoma patients with different HPV status[J]. Pol J Pathol，2021，72(4)：296-314.

P4HA2 promotes proliferation of esophageal squamous carcinoma cells via activating the EGFR/AKT/S6 signaling pathway

PDF (PC)

Knowledge

Abstract

Cite this article

share this article

References

Related Articles 15

Recommended Articles

Metrics

Comments

[1]	LI Ziyao, ZHANG Haiping, MADINIYET·Niyaz, JULATI·Ainiwaer, ZHANG Liwei, EDRIS·Awut. Clinicopathological significance of cystatin 6 protein expression in Kazakh esophageal squamous cell carcinoma [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2022, 34(6): 429-433,438.
[2]	ZHANG Junjun, LIANG Leping. Effect of PTEN C-tail on migration and proliferation of nasopharyngeal carcinoma cells [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2022, 34(6): 434-438.
[3]	CUI Wenxuan, JIAO Wenjing, ZHAO Wei, DU Yanyan, TIAN Guo, ZHANG Jinyan, MA Ming. Clinical values of combined FIB, FAR and serum tumor markers in diagnosis and progression of ESCC patients [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2022, 34(4): 289-294,326.
[4]	ZHANG Yue, WANG Yaoyi, WU Xueliang, ZHANG Zhisheng, YANG Xiuming, JIANG Yang, QIAO Zhifei, LIANG Wanping, XUE Jun. The combination of ¹²⁵I particles and AZD1152 efficiently inhibited proliferation and promoted apoptosis of a triple negative breast cancer cell line [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2022, 34(4): 295-299,306.
[5]	ZHAO Yan, SUN Zhenxiao. Metformin inhibitd proliferation and migration of human breast cancer cell in vitro [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2022, 34(1): 35-39.
[6]	YANG Xingxiao, ZHANG Xueyuan, ZOU Naiyi, SHAN Bao'en, MA Ming, ZHU Shuchai. Effects of HMGB1 silencing on migration, invasion and radiosensitivity of esophageal squamous cell carcinoma cells [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2021, 33(5): 327-333.
[7]	YANG Liyan, LIU Zou, HAO Jiajie, ZHANG Yu, WANG Mingrong. Study on the mechanism of nucleo-plasma translocation of p62 protein in esophageal squamous cell carcinoma [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2021, 33(5): 338-344.
[8]	CHANG Chen, YANG Liyan, CAI Hongqing, YUAN Qing, HAO Jiajie, WANG Mingrong. Expressions and clinical implications of SERPINE1 mRNA in esophageal squamous carcinoma tissues [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2021, 33(4): 245-249.
[9]	HUANG Xiaohua, NIU Yongdong, SHI Ganggang. Inhibitory effects and mechanisms of nuclear receptor FXR activation in cervical cancer cell line CaSki [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2021, 33(4): 302-306.
[10]	ZHENG Junwen, CHANG Chen, HAO Jiajie, CAI Yan, WANG Mingrong, ZHANG Yu. Investigation on expression and function of NEDD4 in esophageal squamous cell carcinoma [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2021, 33(3): 203-207,224.
[11]	JIAO Wenjing, GUO Xiujuan, SHAO Junguo, JIAO Wenpeng, ZHANG Jinyan. Relationships among blood cell ratios, clinicopathological characteristics and prognosis in esophageal squamous cell carcinoma [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2021, 33(3): 213-217.
[12]	ZHANG Die, LIU Xianghe, HUO Miaomiao, LIU Mei, XU Ningzhi, ZHU Hongxia. Effects of miR-195-5p on radiosensitivity of esophageal squamous cell carcinoma cells [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2021, 33(2): 81-88,94.
[13]	ZHANG Na, FAN Zhilu, YANG Liyan, CHANG Chen, CAI Yan, HAO Jiajie, WANG Mingrong. Clinical significance of decreased SERPINB5 expression in esophageal squamous cell carcinomas [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2021, 33(2): 101-109.
[14]	LAN Li, CHEN Haili, XU Lei. Mechanism of RBMS3-S3 on the proliferation, apoptosis and invasion of cervical cancer cells [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2020, 32(6): 438-443.
[15]	GULZARIA·Aikula, TAN Yao, PALIDA·Apiziaji. Expression of long non-coding RNAs in esophageal squamous cell carcinoma of Kazak nationality in Xinjiang [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2020, 32(3): 194-197,202.