High expression of PTPRM predicts poor prognosis and promotes tumor growth and lymph node metastasis in cervical cancer

Pan Liu,Jiaming Huang,Chunyu Zhang,Tianyu Liu,Yuandong Liao,Weipeng He,Hao Tan,Shuzhong Yao,Shiyin Ooi,Shuhang Qin,Wei Wang,Junxiu Liu,Meng Xia,Manman Xu,Qiqiao Du,Yuan Zhu,Ming Chen,Qiaojian Zou

doi:10.1038/s41419-020-02826-x

Abstract

The prognosis for cervical cancer (CCa) patients with lymph node metastasis (LNM) is dismal. Elucidation of the molecular mechanisms underlying LNM may provide clinical therapeutic strategies for CCa patients with LNM. However, the precise mechanism of LNM in CCa remains unclear. Herein, we demonstrated that protein tyrosine phosphatase receptor type M (PTPRM), identified from TCGA dataset, was markedly upregulated in CCa with LNM and correlated with LNM. Moreover, PTPRM was an independent prognostic factor of CCa patients in multivariate Cox′s proportional hazards model analysis and associated with poor prognosis. Furthermore, through gain-of-function and loss-of-function approaches, we found that PTPRM promoted CCa cells proliferation, migration, invasion, lymphangiogenesis, and LNM. Mechanistically, PTPRM promoted epithelial–mesenchymal transition (EMT) via Src-AKT signaling pathway and induced lymphangiogenesis in a VEGF-C dependent manner, resulting in LNM of CCa. Importantly, knockdown of PTPRM dramatically reduced LNM in vivo, suggesting that PTPRM plays an important role in the LNM of CCa. Taken together, our findings uncover a novel molecular mechanism in the LNM of CCa and identify PTPRM as a novel prognostic factor and potential therapeutic target for LNM in CCa.

Highlights

Cervicer (CCa) is the fourth most common malignant cancer among females worldwide with approximately 569,847 new cases and 311,365 deaths in 20181
Identification of phosphatase receptor type M (PTPRM) in cervical cancer (CCa) from TCGA dataset We divided the CCa cases (FIGO stage IA2 to IIA) into 2 groups depending on the tumor size: locally advanced CCa (LACC) group (FIGO stage IB2 and IIA2) and early stage CCa (ECC) group (FIGO stage IA2, IB1 and IIA1)
314 genes were upregulated in LACC tissues, of which 44 genes were correlated with poor survival of CCa and another 646 genes were downregulated in LACC tissues, of which 132 genes were correlated with poor survival of CCa

Summary

Introduction

Cervicer (CCa) is the fourth most common malignant cancer among females worldwide with approximately 569,847 new cases and 311,365 deaths in 20181. 90% of cervical cancer occurred in developing countries in 20151,2. Lymph node metastasis (LNM) is a key prognostic factor and the leading cause of death of CCa3–5. Protein tyrosine phosphatase receptor type M (PTPRM) is a member of the PTP family and was reported as a tumor-associated factor which was mutated in many kinds of cancers. It has been reported that increased expression of PTPRM was negatively correlated with the progression of colorectal adenoma-carcinoma, small intestinal neuroendocrine tumors and breast cancer[11,12,13], while the single-nucleotide polymorphisms of the PTPRM suggested it could play an oncogenic role in lung cancer[14].

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Conclusion