Uterine Leiomyoma, or uterine fibroid (ULM), is a benign lesion which arises commonly in the muscular areas of the uterine wall [18]. Uterine leiomyosarcoma (ULMS) is a smooth muscles malignancy that arises in the smooth muscles areas of the uterus [19]. Approximately, among every 1000 women having fibroid, one to five women were found with ULMS too. The prevalence of their occurrence is increasing and till date no effective treatments were found [20]. So, in order to find more efficient methods for treatment, several studies have suggested different pathways and particular genes that are associated with the development of ULMS and ULM. Recently, different bioinformatics studies were used for finding the molecular mechanism of uterine leiomyomas and uterine leiomyosarcoma disease. In this present in silico analysis, the highly efficient screening of gene expressions dataset was performed which revealed a total of 371 DEGs ( 50 ULM and 321 ULMS genes).
On the basis of GO cluster, the main biological processes of DEGs involve cell adhesion, cell motility, cell differentiation, localization of cell in ULMS and cell adhesion, apoptosis, neuronal development, cell morphogenesis in ULM. Major DEGs that formed the hub nodes were eight up regulated genes (KIF5C,ZNF365,EPYC,COL11A1,SHOX2,MMP13,TNN,RNF128) and six down regulated genes(ABLIM1,GRAMD3,GATA3,ABCA8,GPM6A,LMBRD1).
ZNF365 gene was found to be involved in maintenance of stable genome, repairing damaged DNA. Moreover, ZNF365 also promotes recovery of stalled replication fork in order to provide genomic stability which were detected in both hereditary and sporadic cancer types [21]. Variations in ZNF365 gene may increase the risk of having breast cancer through affecting the dense tissues proportion in breast [22]. According to YJhang et al. ZNF365 loss leads to delay in progression of mitosis and this also results in exit due to stress in replication process which leads to increase in aneuploidy, centrosome reduplication and disruption of cytokinesis process [21]. However, this gene mechanism in the case of ULM and ULMS has yet not been identified and since, we speculate that ZNF365 may be closely related with DNA repairing and genome stability thus could be a potent target for ULM and ULMS treatment.
KIF5C gene encodes motor proteins that belong to the kinesin superfamily involved in eukaryotic cell motilities [23]. Tsibris et al., 2003 found the KIF5C gene to be one of the up-regulated genes in uterine fibroid [24]. Artur Padzik et al. revealed that KIF5C protein phosphorylated by JNK alters its cell motility and transport of microtubules loaded with cargoes. Wei Wang et al. suggested from their experiment that among 4 linear transcripts mRNAs KIF5C was an up regulated gene in ULM [25]. However, till date no studies could find the KIF5C gene role in ULMS case. Further, KIF5C gene is associated with cell motility like features and hence may prove to be a novel target for these both ULM and ULMS.
Lisowska et al. recognized EPYC genes associated with LOX were found in disease free survivability with overall survival and disease-free survival in ovarian cancer [26]. EPYC genes encodes for proteoglycan. These help in regulating fibrillogenesis. EPYC gene was found to be involved in breast, uterine, colorectal cancer [27]. Radosław Januchowski et al. found EPYC gene to be upregulated in both cell lines (A2780DR1, A2780DR2) that were DOX resistant [28]. However, till date no studies have reported its function in ULM and ULMS. Since, in different cancers EPYC gene was found to be up regulated and in this present study this gene was found to be up regulated which may help to provide a novel lead for treatment of these uterine tumors.
SHOX2 gene is used to regulate transcription processes and its DNA methylation was found to be the biomarker of lung cancer [29].In breast cancer, S. Hong et al. investigated induction of EMT through SHOX2 overexpression [30]. B. Schmidt et al. identified that methylation of SHOX2 DNA was found as biomarker for lung cancer [31]. Fubiao Ye etal. investigated cell apoptosis and cell proliferation, extracellular matrix formation as major roles of SHOX2 on nucleus pulposus cells [32]. However, SHOX2 role in ULMS and ULM diseases was not found till now. Since in different carcinomas cases its involvement in cell apoptosis and cell proliferation, extracellular matrix formation like processes may provide a biomarker for the treatment of both ULMS and ULM also.
TNN gene encodes proteins involved in cell migration [33]. In tumors it stimulates angiogenesis of endothelial cells. It was also found to be one of the biomarkers for breast cancer [34].According to Leif E.Peterson et al., the TNN gene is involved in cell matrix adhesion in lung adenocarcinoma [35]. Baolin Liu et al investigated that cancer genes like TNN were found to be involved in extracellular matrix interactions like pathways [36]. However, TNN gene was not identified in ULM and ULMS like cases and since it helps in cell matrix adhesion, so it may serve as a promising target for these both cases.
MMP13 encodes protein produced from stromal fibroblast that are involved in degradation of different ECM components and induces angiogenesis by increasing protein levels of VEGF and VEGFR2 [37].According to Sunil K Halder et al. high expression of MMP13 in uterine leiomyoma pathogenesis was detected [38].Though it was not found in ULMS cases. And according to Guillaume E Courtoy et al. MMP13 encoded proteins were involved in apoptosis, cell proliferation in myoma [39]. And this may provide a potential lead for treatment ULMS also.
GPMA6 gene encodes protein involved in neuronal differentiation and development. These encoded proteins helps in neuronal stem cells migration [40]. GPMA6 gene was found to be novel target gene involved in proliferation, promoting tumor survival and development in thyroid carcinomas [41]. And these features of GPMA6 gene would help to provide novel candidate for both ULM and ULMS.
According to Xuhui Liu et al., the COL11A1 gene was identified as a marker for uterine fibroid via gene expression analysis. COL11A1 gene encoding proteins was found in focal adhesion and extracellular matrix receptor interactions which suggests to be involved as biomarkers in leiomyoma cases [42]. However, it was not found to be involved in leiomyosarcomas. However the features of focal adhesion and ECM receptor interactions of this gene may help to identify a potent marker for ULMS.
RNF128 (also called as Grail) is ubiquitin E3 ligase and plays a vital role in producing cytokines [43]. Yi-Ying Lee et al. suggested that RNF128 downregulation was involved in urothelial cancer [44]. Miika Mehine et al. investigated through integrated ULM dataset analysis that RNF128 to be one of the markers for ULM [45]. Though none of the studies revealed its connection with ULMS but being p53 interacting glycoprotein and under stress conditions becomes crucial for apoptosis induced by p53 may also help to identify a key biomarker for ULMS cases.
GATA2 was found to be involved in cell proliferation and cell cycle regulation. Recently Shan Yu et al. found that GATA2 as one of the markers for breast cancer [46]. Shun Sato et al. through their bioinformatics studies found that GATA2 was a biomarker of uterine fibroid [47]. Veronica Rodriguez-Bravo et al. have reported GATA2 gene aggressiveness in prostate cancer due to its overexpression leads to increase in proliferation, invasiveness [48]. Since no any study revealed the GATA2 role in ULMS hence GATA2 gene can be thought to play an important role in cell proliferation and can be considered as a novel candidate for ULMS cases.
Lisa Golmard et al. suggested that RAD51B mutation correlated with breast and ovarian cancer. These genes were found to be involved in DNA repair mechanism [49]. Zehra Orduluet al. revealed RAD51B to be one of the biomarkers for uterine fibroid [50]. Javier A. Arias-Stella et al. identified RAD51B as one of the biomarkers in uterine myxoid leiomyosarcomas [51]. Since, RAD51B correlation with both ULM and ULMS may prove to be a potent marker for their treatment.
According to Niko Välimäk et al. found ESR1 as one of the potential markers in uterine fibroid diseases [52]. Mostafa A. Borahay et al. revealed the different estrogen signalling pathways involving ESR1 to be responsible in uterine leiomyoma diseases [53]. Recent studies of Adi Zundelevich et al. reported correlation of ESR1 mutation and breast cancer [54]. Heather Miller et al. also investigated estrogen receptor involvement in uterine leiomyosarcomas [55]. Thus, ESR1 correlation with both ULM and ULMS cases may provide potential key markers for their treatment.
Madhura Joglekar-Javadekar et al. suggested that PDGFRA mutation leads to hepatocellular carcinoma, leukemias, gastrointestinal stromal tumors (GISTs) and glioblastoma [56]. Guangli Suo et al. found the PDGFRA gene to be involved in different signalling pathways and in growth of uterine smooth muscles [57]. Its overexpression may lead to uterine leiomyoma. Juhasz-Böss also reviewed PDGFRA correlation with ULMS. So, PDGFRA gene might provide a biomarker for treatment of both ULM and ULMS.
In this microarray analysis NM, ULM and ULMS tissues has been used which provides an integrated approach to study the synergistic effect of differential gene expression on several biological processes and pathways to reveal their mechanism at molecular level.