4.1. Breast CancerThe most common cancer detected in women with distant metastasis and poor prognosis is breast cancer. Studies have found it to be the second largest cause of death amongst female cancer patients [35]. A study conducted in 1998 reported an increase in the mRNA expression of ST3GAL2 in breast cancer stem cells is linked to increased gangliosides expression. A high expression of ST3Gal3 was found to be positively correlated with the number of axillary lymph nodes and reduced patient overall survival [36]. MUC1 is a membrane protein expressed on the luminal surface of simple epithelial cells. It has a large Extracellular Domain (ECD) consisting of repeated amino acids, each comprising five potential sites for O-glycosylation. In normal breast epithelial cells, the glycosylate units of MUC1 are transformed from core1 to core2 glycans, followed by adding polylactosamine units. However, this conversion is reduced in breast cancer cells, resulting in shorter O-glycan chains with increased sialic acid content. In a study, the staining intensity of Maakia amurensis lectin (2,3 linked sialic acid) and ST3Gal I expression was shown to be strongly positively correlated (p = 0.0015), demonstrating a direct linkage between an increase in sialic acid structures and ST3Gal1 mRNA expression [37]. It has also been determined that there is a strong association between ST3Gal3 expression and SLeX synthesis levels, which controls the ability of cells to adhere to rh-E selectin. This resulted in the conclusion that ST3Gal3 overexpression increases cell migration and invasiveness (p = 0.05) [24]. In TNBC patients, a different study found a positive correlation between high ST6GAL1 mRNA expression and a favorable relapse-free survival (RFS) rate [38]. Furthermore, knocking down ST6GAL1 with shRNA targeted to the various ST6GAL1 sites significantly reduced the aggressive breast cancer cells’ capacity to proliferate and invade. ST6GAL2 expression is associated with poor prognosis for patients [14]. Moreover, silencing ST6GAL2 in breast cancer cells reduced xenograft tumor growth in vivo [14]. Along with its presence throughout the Golgi stacks in the transfected cells, ST6GalNAc1 is seen to play a role in the core1/core2 pathway (described above) [39]. A subsequent result also established a correlation between the expression of hST6GalNAc-I and STn and concluded the expression of STn in breast cancer cells transfected with the enzyme. Additional research validated the role of ST6GalNAc2 as a novel metastasis suppressor by correlating its high expression level with increased patient survival [40] and reveals the overexpression of ST6GalNac5 leads to a decreased adhesion [41]. TNBC patients showed a connection between increased STSia8 expression and poor overall survival (OS) and disease-free survival (DFS) in a different study [42]. While there was no statistically significant difference in ER-negative people, increased ST8Sia1 mRNA expression was associated with improved disease-free survival [43]. Additionally, ST8Sia1 was silenced to limit tumor growth in a xenograft model, and ST8Sia1 was downregulated by triptolide to suppress tumor growth and lengthen survival [44]. Finally, it has been discovered that ST8Sia4 is overexpressed and aids in the development of breast cancer [16].Suppression of NEU1 demonstrates the correlation with a decrease in cell proliferation and apoptosis enhancement by the activation of caspase3 [45]. NEU3 silencing caused apoptosis without specific stimuli [46]. 4.2. Pancreatic CancerPDAC (pancreatic ductal adenocarcinoma) has a poor 5-year survival rate of fewer than 9 percent, making it one of the fatal cancers. According to recent research, ST6Gal-I, a glycosyltransferase, supports CSC (cancer stem cells) traits and functions as a survival factor to shield cells from cytotoxic assaults such as chemotherapy, radiation, and serum deprivation, and hypoxia [47,48,49,50]. In many malignancies, including ovarian, pancreatic, and colon tumors, ST6Gal-I is elevated, and high production of this enzyme is associated with a bad prognosis for the patient [51,52,53]. Pancreatic Intraepithelial Neoplasia (PanIN) has significant ST6Gal-I expression, but normal pancreatic acinar cells do not exhibit ST6Gal-I protein expression [51].EGFR is a key factor in driving EMT, and earlier research has shown that sialylation of EGFR by ST6Gal-I encourages both basal and ligand-dependent EGFR activation in pancreatic and ovarian cancer cells [54]. The EGFR inhibitor, Erlotinib, has been approved by the US Food and Drug Administration to treat PDAC in combination with gemcitabine since EGFR is elevated in about 85% of patients with PDAC [55]. According to research, which showed that EGFR activation in various cancer cell lines was α2-6 sialylation-dependent, ST6Gal-I OE in Suit2 cells increased α2-6 sialylation and basal EGFR activation, whereas ST6Gal-I KD in S2-013 and S2-LM7AA decreased EGFR sialylation and activation. Notably, erlotinib treatment removed sialylation-dependent variations in EGFR activation and reversed the effects of ST6Gal-I on the expression of EMT markers and cell invasiveness in the Suit2 and S2-LM7AA lines. These findings provide compelling evidence for the idea that sialylated EGFR participates in the EMT-promoting effect of ST6Gal-I [56].Studies have shown that greater 2,3- and 2,6-linked sialic acids (SAs) are found in pancreatic cancer cells, which most contribute to the disease’s higher risk of metastasis [57]. Lysosomal (Neu1), cytosolic (Neu2), membrane-bound (Neu3), and luminal (Neu4) sialidases are the four sialidases found in mammalian cells. They differ in their enzymatic properties and substrate specificity. They act differently throughout carcinogenesis and are crucial for the equilibrium of sialylation [46,58]. After comparing the status of Neu1/Neu2/Neu3/Neu4 in cancer and then in normal tissue specimens, it was concluded that the loss of Neu2 may aid in greater sialylation status in pancreatic cancer manifestation [59]. According to several findings, greater sialylation status influences the ST3GalIII and 2,3 sialyltransferase galactosyl transferases in PDAC, which in turn affects cell motility, adhesion, and metastasis [60]. In response to apoptotic triggers such as serum deprivation, which drastically decreased the growth rate, Neu2 overexpression displayed apoptosis vulnerability. More importantly, this event affected crucial cell cycle regulatory molecules, increased the expression of pro-apoptotic and decreased the expression of anti-apoptotic proteins, pushing Neu2-overexpressed cells toward apoptosis as indicated by an increased number of cells in the late apoptotic stage. It is interesting to note that in pancreatic cancer, α2,3linked SAs are thought to be the primary substrate for Neu2 [59]. 4.3. Ovarian CancerOvarian cancer is amongst the most common cancers affecting females around the world and is accompanied by an extremely poor prognosis and significantly higher death rates [61]. A large number of studies suggest that targeting the sialyltransferases and neuraminidases might be a potential strategy to prevent metastasis in this particular cancer. One such study involving qRT-PCR, western blotting, and immunohistochemistry assessed the expression of sialyltransferase ST3GAL1 in ovarian cancer tissue and cell lines and found it to be upregulated. Their results also indicated that overexpressing ST3GAL1 promoted cell growth, migration, and invasion in ovarian cancer cells, whereas inhibiting STG3GAL1 expression had the opposite results. They also investigate ST3GAL1′s participation in EMT via various studies and conclude that it can influence the level of cell migration and invasion induced by TGF-β1 [23]. Higher expressions of ST3GAL1 have also been found to be related to the advanced stage serous type epithelial ovarian cancer (EOC), and the process of a2,3-linked sialylation is highly important for clear cell type epithelial ovarian cancer (C-EOC) with the potential for a possible therapeutic solution [62].In recent years, a large number of studies have suggested that upregulation of ST6GAL1 has been associated with tumor aggressiveness in various cancers. Such studies conducted for ovarian cancers using mRNA expression data suggest a strong correlation between high ST6GAL1 expression and lymphatic invasion of tumor cells, while western blot analysis of ST6GAL1 protein levels has suggested that patients diagnosed with distant metastasis often present significantly higher ST6GAL1 protein levels. The study further claims to be a promising therapeutic target, and metastasis formation might be decreased by blocking it due to its influence on hallmarks of the carcinogenic phenotype like adhesion, metastasis formation, and chemoresistance [63]. Studies have also described ST6GAL1′s complex relationship with Sox2, a master stem cell transcription factor. Located within the 3q26 amplicon, they are amplified in cancer cells, and due to the binding of the transcribed Sox2 to ST6GAL1, its expression is enhanced further. These events aid in the remodeling of cancer cells into a more stem-like cell phenotype, which itself is associated with ovarian cancer progression and recurrence [64]. Other sialyltransferases and their roles in the progression of ovarian cancer have also been explored. One such sialyltransferase is ST3GAL3, whose mRNA expression levels differed significantly amongst different ovarian cancer cell lines. HO8910PM with high invasive and metastatic capacity expressed elevated ST3Gal3 mRNA and displayed high chemoresistance to cisplatin, while in the case of SKOV3 cells, which have lower expression levels of ST3Gal3 show more chemo-sensitive to cisplatin. Their findings light on the reverse correlation between the expression levels of ST3GAL3 and the dosage of cisplatin used in various cell lines and claim that by targeting ST3GAL3, chemoresistance of cisplatin can be prevented the relapse of ovarian cancer [64]. Similar studies conducted have held ST3GAL3 accountable for paclitaxel-related resistance during ovarian cancer chemotherapy. They further suggest that overexpression of ST3Gal3 may serve as a diagnostic and prognostic marker and also a potential chemotherapeutic target for ovarian cancer [65]. Fewer studies also elaborate on the role of neuraminidases in ovarian cancer, one being where higher expression of NEU1 in ovarian cancer tissues of patients in comparison to adjacent normal tissues was noted. They further elucidate the role of NEU1 siRNA, which via targeting lysosome and oxidative phosphorylation signaling, effectively inhibits the proliferation, apoptosis, and invasion of human ovarian cancer cells suggesting NEU1 can be targeted for the treatment of ovarian cancer [66]. 4.4. Other CancersCytokines such as IL3 and CCL17, secreted by M2 macrophages co-cultured with colon cancer, induce expression of ST6GalNAc1, which results in higher expression of sTn antigen inducing on MUC1 [67]. ST6GalNAc6 downregulation in colon cancer is associated with epigenetic silencing, paralleled by decreased disialyl LeA expression with a concomitant increase in sialyl LeA [68]. Decreased expression of ST8Sia5 is associated with gene regulation by fork-head box O3 (FOXO3), the functional deficiency of which facilitates inflammation-mediated colon cancer growth linked to poor survival in patients [69]. In prostate cancer, high ST6Gal-I expression positively correlates with Gleason scores, seminal vesicle involvement, and poor survival in patients [70]. Shorter isoforms of ST6GalNAc1 (induced by androgens) exhibit a similar sialyltransferase activityClick or tap here to enter text., the former is responsible for expressing the sTn antigen [71]. ST6GalNAc3 is shown to be hypermethylated. However, it is not yet known if this epigenetic silencing contributes to the development of cancer [72]. In gastric cancer, ST3Gal4 contributes to poor prognosis and selectin-dependent adhesion through sLex, whereas ST6GalNAc 1 induces expression of sTn antigen and regulates the gene expression of IGF-1 through STAT5b activation [26,73]. ST6Ga1 expresses CDw75 antigen (a sialylated carbohydrate epitope), which strongly correlates with aggressive gastric tumors [74]. Other than this, ST6Gal1 and ST3Gal3 expression has also shown an association with secondary local tumor recurrences in gastric cancer (p = 0.005; p = 0.012) [75]. In renal cancer, silencing ST6GalNAc6 increases the metastatic capability of tumor cells, expressing low levels of DSGb5, and decreasing migration, but not proliferation [76].Another cancer with an increasing incidence and extremely high mortality rates is the one primarily affecting Esophagus [77]. Significant downregulation of ST6GALNAC1 in Esophageal Squamous Cell Carcinoma (ESCC) tissues in comparison to normal tissues via hyper-methylation and loss of heterozygosity have been reported, possibly making ST6GALNAC1 a candidate responsible gene for ESCC [78]. Another study conducted with Cancer Stem Cells (CSCs), the primary cause of cancer recurrence and metastasis, found ST8SIA2 to be hypermethylated in ESCC-CSCs. Further analysis conducted with GEPIA also revealed ST8SIA2 to be highly expressed in ESCC tissues in comparison to normal tissues and also correlated with poor disease-free survival [79]. Another study involving Adenoviral- fragile histidine triad (Ad-FHIT) treatment of esophageal cancer cells found overexpression of ST3GAL6 in apoptotic cells compared with non-apoptotic cells, suggesting Ad-FHIT treatment’s role in the inhibition of a sialyltransferase-associated metastasis [80]. mRNA expression analysis of various sialyltransferases and neuraminidases was conducted using RT-qPCR in Oral Squamous Cell Carcinoma (OSCC), found sialyltransferases ST3GAL1, ST3GAL2, ST3GAL3, ST3GAL4, ST3GAL6, and ST6GAL1 and neuraminidase NEU3 to be downregulated in tumor tissues in comparison to normal. Further analysis revealed the correlation between elevated levels of ST3GAL2 and ST3GAL3 with metastasis and progression of OSCC [81].In the case of Head and Neck Squamous Cell Carcinoma (HNSCC), elevated mRNA levels of NEU3 were found in tumor tissues in comparison to normal tissues. The elevation was also found to be associated with lymph node metastasis, which is an important event for HNSCC progression and is often related to higher mortality rates. Further studies to understand the underlying mechanism reveal that NEU3 participates in HNSCC progression through EGFR signaling regulation and can be targeted to inhibit the disease progression [82]. Studies have revealed that cell adhesion and invasion in Anaplastic Large Cell Lymphoma (ALCL) are regulated by the process of sialylation involving ST6Gal1 and N-glycans. Galectin-8 causes the growth inhibition of lymphoma cells induced by neuraminidase treatment [83]. Another study’s findings suggest that in the case of lymphoreticular malignancies, an increase in sialyltransferase activity is observed [84].Sialyltransferase studies revolving around various types of skin cancers have also surfaced, especially around melanoma, the most serious form of skin cancer. Studies report that ST3GAL1 promotes melanoma metastasis via AXL and also acts as a target for the oncogenic SOX2-GLI1 transcriptional complex [85]. A study involving the evaluation of sialyltransferase expression in actinic keratosis, keratoacanthoma, squamous cell carcinoma, and basal cell carcinoma found elevated levels of ST3Gal1 and ST6Gal1 to be associated with skin tumors with greater potential for invasion and metastasis [86]. The most frequent malignant tumor of the urinary system is Bladder Cancer (BLCA), and the leading cause of death from the disease is distant metastasis. Data from the Gene Expression Profiling Interactive Analysis and TCGA databases revealed that ST8SIA1′s mRNA expression levels were lower in BLCA tissues than in healthy tissues, and this was further supported by immunohistochemistry and western blot analysis. The pathogenic grade and invasiveness of BLCA were adversely correlated with the ST8SIA1 expression levels. Western blot analysis showed that BLCA cell lines expressed ST8SIA1 at lower levels than a typical urothelial cell line. The proliferation, migration, and invasion of T24 and 5637 BLCA cells were inhibited by ST8SIA1 overexpression, according to CCK-8, flow cytometry, wound healing, colony formation, and Transwell experiments. Further research showed that ST8SIA1 might reduce the production of JAK/STAT pathway-targeting signal molecules such as MMP2, proliferating cell nuclear antigen, cyclin D1, and Bcl2 in two BLCA cell lines, as well as suppress the phosphorylation of JAK2 and STAT3. This gave researchers a fresh target for the detection and therapy of BLCA [87]. One of the most common tumors that kill female patients is Cervical Cancer, which also has the second-highest mortality rate among cancers in underdeveloped nations [88]. Cervical cancer has been shown to be brought on by Human Papillomavirus (HPV) infection [89]. Recent research showed that ST3Gal IV levels were lower in cervical cancer tissues than in nearby tissues and were inversely linked with the tumor’s aggressiveness. In vitro and in vivo, ST3Gal IV overexpression reduced the growth and division of cervical cancer HeLa and SiHa cells. Additionally, ST3Gal IV overexpression increased the expression of various Notch pathway constituents, including Jagged1, Notch1, Hes1, and Hey1, while decreasing the expression of cell cycle proteins, including Cyclin D1, Cyclin E1, CDK2, and CDK4. These findings suggest that the Notch/p21/CDKs signaling pathway negatively regulates cell proliferation in cervical cancer by reducing ST3Gal IV expression. As a result, ST3GalIV may be a target for the detection and treatment of cervical cancer [90].A hematopoietic stem cell condition called Chronic Myeloid Leukemia (CML) results from a translocation of chromosomes 9 and 22′s long arms, which contains the BCR-ABL fusion oncogene. Recent studies have shown that ST8SIA4 mRNA had the highest level of expression and was a major factor in the high levels of 2,8-linked NeuNAc residues on the PBMC surfaces of CML/MDR patients, but ST8SIA6 expression was at a high level in CML patients, indicating ST8SIA6 to be an essential factor in the emergence of malignant changes. In CML cell lines, ST8SIA4 altered expression significantly reduced PI3K/Akt pathway activity [91]. Additional research showed that altered ST3GALIV expression had a substantial impact on the distribution of the cell cycle, the apoptotic signal, and cell proliferation [92].According to a recent study, ST6GAL1 levels dramatically rose, whereas ST3GAL1, ST6GALNAC3, and ST8SIA6 levels were noticeably decreased in lung cancer tissues and cells. Lung cancer tissues and cells have increased ST6Gal-I mRNA, protein, and glycan levels. Additionally, down-regulating ST6Gal-I reduced the levels of the proteins Jagged1, DLL-1, Notch1, Hes1, Hey1, Matrix-Metalloproteinases (MMPs), and VEGF. It also inhibited the ability of A549 and H1299 cells to proliferate, migrate, and invade in vitro. Additionally, ST6Gal-I silencing of A549 and H1299 cells resulted in reduced proliferation and metastasis, which was reversed by Notch1 overexpression. This suggests that ST6Gal-I may mediate the invasiveness and tumorigenicity of NSCLC cells via the Notch1/Hes1/MMPs pathway both in vitro and in vivo. Modification of 2,6-sialylation is positively associated with lung cancer development [93].