Molecular profiling of tumour budding implicates TGFβ-mediated epithelial-mesenchymal transition as a therapeutic target in oral squamous cell carcinoma.

Although tumour budding is an adverse prognostic factor for many cancer types, the molecular mechanisms governing this phenomenon are incompletely understood. Therefore, understanding the molecular basis of tumour budding may provide new therapeutic and diagnostic options. We employ digital image analysis to demonstrate that the number of tumour buds in cytokeratin-stained sections correlates with patients having lymph node metastases at diagnosis. The tumour bud count was also a predictor of overall survival, independent of TNM stage. Tumour buds and paired central tumour areas were subsequently collected from oral squamous cell carcinoma (OSCC) specimens, using laser capture microdissection, and examined with RNA sequencing and miRNA-qPCR arrays. Compared with cells from the central parts of the tumours, budding cells exhibited a particular gene expression signature, comprising factors involved in epithelial-mesenchymal transition (EMT) and activated TGFβ signalling. Transcription factors ZEB1 and PRRX1 were up-regulated concomitantly with the decreased expression of mesenchymal-epithelial (MET) transcription factors (eg OVOL1) in addition to Krüppel-like factors and Grainyhead-like factors. Moreover, miR-200 family members were down-regulated in budding tumour cells. We used immunohistochemistry to validate five markers of the EMT/MET process in 199 OSCC tumours, as well as in situ hybridization in 20 OSCC samples. Given the strong relationship between tumour budding and the development of lymph node metastases and an adverse prognosis, therapeutics based on inhibiting the activation of TGFβ signalling may prove useful in the treatment of OSCC.

Jensen DH ，Dabelsteen E ，Specht L ，Fiehn AM ，Therkildsen MH ，Jønson L ，Vikesaa J ，Nielsen FC ，von Buchwald C ... -  《-》

miR-654-5p Targets GRAP to Promote Proliferation, Metastasis, and Chemoresistance of Oral Squamous Cell Carcinoma Through Ras/MAPK Signaling.

Lu M ，Wang C ，Chen W ，Mao C ，Wang J ... -  《-》

Ultra-deep targeted sequencing of advanced oral squamous cell carcinoma identifies a mutation-based prognostic gene signature.

Chen SJ ，Liu H ，Liao CT ，Huang PJ ，Huang Y ，Hsu A ，Tang P ，Chang YS ，Chen HC ，Yen TC ... -  《Oncotarget》

MicroRNA-155-5p is associated with oral squamous cell carcinoma metastasis and poor prognosis.

Abnormal miRNA expression was recently implicated in the metastasis of oral squamous cell carcinoma (OSCC) and with a poor prognosis. The initiation of the invasion-metastasis cascade involves epithelial-mesenchymal transition (EMT). Our aim was to clarify how miRNA, especially miR-155-5p misexpression contributes to OSCC metastasis through EMT. We collected tumor samples from 73 subjects with OSCC. The samples were analyzed by quantitative reverse-transcription polymerase chain reaction (qRT-PCR), and correlations between miR-155-5p levels and clinical characteristics were investigated. OSCC cell lines were analyzed by miRNA microarray and by transfection with a miR-155-5p mimic or inhibitor, followed by proliferation and wound-healing migration assays. qRT-PCR analyses of EMT makers in cells transfected with miR-155-5p inhibitor were performed. We found high miR-155-5p expression in tissue samples from subjects with OSCC that had metastasized to cervical lymph nodes. HSC-3 cells also strongly expressed miR-155-5p. The epithelial marker E-cadherin was strongly expressed in HSC-3 cells transfected with miR-155-5p inhibitor, and we observed elevated SOCS1 and decreased STAT3 expression in these cells. Our results suggest that miR-155-5p causes OSCC to metastasize, and could serve as a novel therapeutic target for OSCC.

Baba O ，Hasegawa S ，Nagai H ，Uchida F ，Yamatoji M ，Kanno NI ，Yamagata K ，Sakai S ，Yanagawa T ，Bukawa H ... -  《-》

Loss of RUNX3 expression inhibits bone invasion of oral squamous cell carcinoma.

Park J ，Kim HJ ，Kim KR ，Lee SK ，Kim H ，Park KK ，Chung WY ... -  《Oncotarget》