miR-138-5p-mediated HOXD11 promotes cell invasion and metastasis by activating the FN1/MMP2/MMP9 pathway and predicts poor prognosis in penile squamous cell carcinoma.

Abstract

The presence and extent of regional lymph node and distant metastasis are the most fatal prognostic factors in penile squamous cell carcinoma (PSCC). However, the available biomarkers and detailed mechanisms underlying the metastasis of PSCC remain elusive. Here, we explored the expression landscape of HOX genes in twelve paired PSCC tissues, including primary tumors, metastatic lymph nodes and corresponding normal tissues, and highlighted that HOXD11 was indispensable in the progression of PSCC. HOXD11 was upregulated in PSCC cell lines and tumors, especially in metastatic lymph nodes. High HOXD11 expression was associated with aggressive features, such as advanced pN stages, extranodal extension, pelvic lymph node and distant metastasis, and predicted poor survival. Furthermore, tumorigenesis assays demonstrated that knockdown of HOXD11 not only inhibited the capability of cell proliferation, invasion and tumor growth but also reduced the burden of metastatic lymph nodes. Further mechanistic studies indicated that miR-138-5p was a tumor suppressor in PSCC by inhibiting the translation of HOXD11 post-transcriptionally through binding to the 3' untranslated region. Furthermore, HOXD11 activated the transcription of FN1 to decompose the extracellular matrix and to promote epithelial mesenchymal transition-like phenotype metastasis via FN1/MMP2/MMP9 pathways. Our study revealed that HOXD11 is a promising prognostic biomarker and predicts advanced disease with poor outcomes, which could serve as a potential therapeutic target for PSCC.

• Authors: Xingliang Tan, Zhenhua Liu, Yanjun Wang, Zhiming Wu, Yuantao Zou, Sihao Luo, Yi Tang, Dong Chen, Gangjun Yuan, Kai Yao
• Journal: Cell death & disease (Cell Death Dis) Vol. 13 Issue 9 Pg. 816 (09 23 2022) ISSN: 2041-4889 [Electronic] England
• PMID: 36151071 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• 3' Untranslated Regions
• MIRN138 microRNA, human
• MicroRNAs
• Transcription Factors
• MMP2 protein, human
• Matrix Metalloproteinase 2
• MMP9 protein, human
• Matrix Metalloproteinase 9

Topics

• 3' Untranslated Regions
• Carcinoma, Squamous Cell (pathology)
• Cell Line, Tumor
• Cell Movement (genetics)
• Cell Proliferation (genetics)
• Gene Expression Regulation, Neoplastic (genetics)
• Genes, Homeobox
• Humans
• Male
• Matrix Metalloproteinase 2 (genetics, metabolism)
• Matrix Metalloproteinase 9 (genetics, metabolism)
• MicroRNAs (genetics, metabolism)
• Penile Neoplasms (genetics, pathology)
• Transcription Factors (metabolism)