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  • br Conclusions and future perspectives br Declarations of in

    2021-10-12


    Conclusions and future perspectives
    Declarations of interest
    Acknowledgements The authors thank Mrs. Kamala Pandey for the help in the preparation of this manuscript. This work was supported by NIH grants R01HL057531 and R01HL062147.
    Introduction Separation of short exons by long non-coding introns is the description of eukaryotic genome. Removal of introns and joining exons together are occurred after splicing [1]. Following alternative splicing, approximately 95% of human genes transcribe more than one transcript and produce variant protein isoforms with similar or entirely different functions, [[2], [3], [4]]. RNA splicing might be tissue dependent [5]. Different molecular mechanisms are involved in the regulation of gene X-Gal australia including epigenetic modulation, microRNAs and alternative splicing, [6]. Normal cell differentiation and growth, migration, cell-to-cell communication and cell death are regulated by an alternative splicing [7]. Therefore, abnormal alternative splicing can disturb normal cellular function and thus cell growth [7]. So extensive alterations in splicing is one of the molecular indicator for human cancers [8]. Transcriptome analysis of different types of cancer revealed an abnormal splicing patterns in the malignant tissues [[9], [10], [11]]. An alternative X-Gal australia splicing has substantial effect on the cell genesis and development of breast cancer such as tumor progression or suppression, some spliceosomal proteins or some other RNA-binding proteins [12]. Recent studies have shown that Soluble guanylyl cyclase, sGC (EC 4.6.1.2), has an important effect on the progression of breast cancer [[13], [14], [15], [16], [17]]. It has been shown that sGC activity has been regulated by an alternative splicing [18]. Mammalian sGC is a heterodimeric enzyme, comprising α1 and β1 subunits; although, α2 and β2 subunits have also been recognized. It is activated by binding of NO to heme moiety [19,20]. The C-terminal domain of α and β subunits is necessary to form a functional catalytic site with low cyclic guanosine monophosphate (cGMP)-forming activity, although NO receptor portion of sGC, located in the N- terminal domain of β subunit, is essential for the enzyme activity, NO binds to heme moiety with high affinity [21]. NCBI (National Center for Biotechnology Information) nucleotide database identifies seven alternatively spliced transcripts for α1 subunit (_1-Tr1 to 1-Tr7) and six for β1 subunit (_1-Tr1 to _1-Tr6) [18]. Expression of several sGC splice forms modulate sGC function and it's enzymatic properties [[22], [23], [24]]. Alteration in sGC splicing may be occur in some illnesses such as cancer and heart disease [18,25]. Alternative splicing in sGC and its biological role have not been previously studied in the breast cancer, although alteration in sGC splicing affected by hydrogen Peroxide, has been shown in MDA-MD-468 cancer cell line [25]. Therefore, the present study was designed to investigate the pattern of expression in the alternative splicing of α1 and β1 sGC in the malignant, benign and normal breast tissues.
    Material and method
    Results
    Discussion There are Growing evidences to suggest that NO/cGMP signaling pathway is related to the development of different cancers, such as breast cancer [15,17,[27], [28], [29]]. Soluble guanylate cyclase (sGC) is encoded by separate genes and can be regulated independently, although heterodimeric form of sGC is necessary for the enzyme activity [13]. Therefore, an alternative splicing could generate different isoforms. Alternative splicing regulates mRNA expressions and several changes in alternative splicing have been known as a hallmark of cancer [30]. Different studies have revealed that an alternative splicing has a key role in the regulation of cGMP and NO/cGMP signaling pathways, such as cGMP-dependent protein kinase I [31] and cGMP-dependant phosphodiesterase (PDE) [32,33]. It has been shown that α1sGC splicing regulates human sGC activity and higher expression of various splice forms have been described in some tissues [24]. Expression and regulation of sGC subunit can be affected by different situations in the cancer cells such as epigenetic [13] and alternative splicing (present findings).