Although squamous cell carcinomas (SCC) are the most frequent human solid tumor at many anatomic sites, the driving molecular alterations underlying their progression from precursor lesions are poorly understood, especially in the context of photodamage.,Therefore, we used high-depth, targeted next-generation sequencing (NGS) of RNA and DNA from routine tissue samples to characterize the progression of both well- (cutaneous) and poorly-studied (ocular) SCCs.,We assessed 56 formalin-fixed paraffin-embedded (FFPE) cutaneous lesions (n= 8 actinic keratosis [AK], n= 30 carcinoma in situ [CIS], n= 18 invasive) and 43 FFPE ocular surface lesions (n= 2 conjunctival/corneal intraepithelial neoplasia [CIN], n= 20 CIS, n= 21 invasive), from institutions in the US and Brazil.,An additional 7 cases of advanced cutaneous SCC were profiled by hybrid-capture-based NGS of >1,500 genes.,The cutaneous and ocular squamous neoplasms displayed a predominance of UV signature mutations.,Precursor lesions had highly similar somatic genomic landscapes to invasive SCCs, including chromosomal gains of 3q involving SOX2, and highly recurrent mutations and/or loss of heterozygosity events affecting tumor suppressors TP53 and CDKN2A.,We identify a novel molecular subclass of CIS with RB1 mutation.,Among TP53 wild-type tumors, human papillomavirus (HPV) transcript was detected in one matched pair of cutaneous CIS and invasive SCC.,Amplicon-based whole-transcriptome sequencing of select 20 cutaneous lesions demonstrated significant upregulation of pro-invasion genes in invasive cutaneous SCCs relative to precursors, including MMP1, MMP3, MMP9, LAMC2, LGALS1, and TNFRSF12A.,Together, ocular and cutaneous squamous neoplasms demonstrate similar alterations, supporting a common model for neoplasia in UV-exposed epithelia.,Treatment modalities useful for cutaneous SCC may also be effective in ocular SCC given the genetic similarity between these tumor types.,Importantly, in both systems, precursor lesions possess the full complement of major genetic changes seen in SCC, supporting non-genetic drivers of invasiveness.
Cutaneous squamous cell carcinoma (SCC) is the second most common human skin cancer with a rapidly increasing incidence among the Caucasian population.,Among the many regulators, responsible for cancer progression and growth, microRNAs (miRNA) are generally accepted as key players by now.,In our current study we found that microRNA-181a (miR-181a) shows low abundance in SCC compared to normal epidermal skin.,In vitro, miRNA downregulation in normal primary keratinocytes induced increased proliferation, while in vivo miR-181a downregulation in HaCaT normal keratinocytes showed tumor-like growth increase up to 50%.,Inversely, upregulation of these miRNAs in cancer cells lead to reduced cellular proliferation and induction of apoptosis in vitro.,An in vivo therapeutic model with induced miR-181a expression in SCC13 cancer cells reduced tumor formation in mice by 80%.,Modulation of miR-181a levels showed an inverse correlation with the proto-oncogene KRAS both on mRNA and protein level by direct interaction.,Knockdown of KRAS mimicked the anti-proliferative effects of miR-181a overexpression in patient-derived SCC cells and abolished the enhanced viability of HaCaT cells following miR-181a knockdown.,Furthermore, phospho-ERK levels correlated with KRAS levels, suggesting that the observed effects were mediated via the MAPK signaling pathway. miR-181a seemed regulated during keratinocyte differentiation probably in order to amplify the tumor suppressive character of differentiation.,Taken together, miR-181a plays a crucial tumor suppressive role in SCC by targeting KRAS and could be a promising candidate for a miRNA based therapy.