Kahari, V.-M. | bioRxiv Science

bioRxiv2023

Clustering of RNA co-expression network identifies novel long non-coding RNA biomarkers in squamous cell carcinoma

Long non-coding RNAs (lncRNAs) have been shown to play an important role in cancer progression. Cutaneous squamous cell carcinoma is the most common metastatic skin cancer with increasing incidence worldwide. The prognosis of the metastatic cSCC is poor, and currently there are no established biomarkers to predict metastatic risk nor specific therapeutic targets for advanced or metastatic cSCC. To elucidate the role of lncRNAs in cSCC, RNA sequencing of patient derived cSCC cell lines and normal human epidermal keratinocytes was performed. The correlation analysis of differentially expressed lncRNA and protein-coding genes revealed six distinct clusters. One of the upregulated clusters involved genes related to cell motility. Upregulation of the expression of lncRNAs involved in cSCC cell motility in cSCC and head and neck SCC (HNSCC) cells was confirmed by qRT-PCR. Upregulation of HOTTIP and LINC00543 was also noted in SCC tumors in vivo and was associated with worse prognosis in HNSCC and lung SCC cohorts in the TCGA data, respectively. Altogether, these results reveal a novel set of lncRNAs involved in cSCC cell locomotion. These lncRNAs may serve as potential novel biomarkers or a biomarker panel and as putative therapeutic targets in locally advanced and metastatic cSCC.

cancer biology↗

bioRxiv2020

Discovery of NOvel CIP2A VAriant (NOCIVA) and its clinical relevance in myeloid leukemias

Cancerous inhibitor of PP2A (CIP2A) is a prevalent human oncoprotein that inhibits tumor suppressor PP2A-B56a. However, CIP2A mRNA and protein variants remain uncharacterized. Here, we report discovery of a CIP2A splicing variant NOCIVA (NOvel CIp2a VAriant). NOCIVA contains CIP2A exons 1-13 fused to a continuous stretch of 349 nucleotide from CIP2A intron 13. Intriguingly, the first 39 nucleotides of the NOCIVA specific sequence are in coding frame with exon 13 of CIP2A, and codes for a 13 amino acid peptide tail unhomologous to any known human protein sequence. Therefore, NOCIVA translates to a unique human protein. NOCIVA retains the capacity to bind to B56a, but whereas CIP2A is predominantly a cytoplasmic protein, NOCIVA translocates to nucleus. Indicative of prevalent alternative splicing from CIP2A to NOCIVA in myeloid malignancies, acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) patient samples overexpress NOCIVA, but not CIP2A mRNA. In AML, high NOCIVA mRNA expression is a marker for adverse overall survival. In CML, high NOCIVA expression associates with inferior event free survival among imatinib treated patients, but not among patients treated with dasatinib or nilotinib. Collectively, we describe discovery of a novel variant of oncoprotein CIP2A, and its clinical relevance in myeloid leukemias. Key PointsO_LIDiscovery and characterization of a first mRNA variant of one of the most prevalently deregulated human oncoproteins CIP2A C_LIO_LIUnlike CIP2A, NOCIVA mRNA is overexpressed in AML and CML patient samples and associates with poor clinical response in both myeloid cancers C_LI

cancer biology↗