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Microbes & Immunity The feature of bladder cancer stem cells

Figure 4. The WNT pathway in bladder cancer stem cells. The complex of WNT, LRP, and Frizzled promotes the translocation of β-catenin into the
nucleus, resulting in the transcription of β-catenin target genes.

and the WNT pathway necessitates further elucidation. is frequently implicated in tumor proliferation and
Currently, numerous drugs targeting the WNT pathway metastasis. Given the regulatory role of the METTL14
are undergoing clinical studies, with WNT antagonists methyltransferase in m A modification, the relationship
6
targeting BCSCs showing promising prospects for research between METTL14 and BCSCs was further investigated.
and development. 62,63 Through sphere-forming assays, Ki67 staining
experiments, and tumor transplantation experiments, the
3.3.3. Notch pathway results demonstrated that METTL14 knockout enhanced
The Notch pathway represents a highly conserved the self-renewal, proliferation, and tumor-initiating ability
signaling pathway that plays a significant role in the self- of BCSCs. Immunoblot analysis measuring the expression
renewal, proliferation, and differentiation abilities of adult levels of target genes in the WNT, Notch, and Hedgehog
stem cells across various tissues. The Notch signaling pathways revealed high expression levels of Notch1 in
pathway primarily consists of Notch receptors, Notch METTL14 knockout cells, with Northern blot experiments
ligands, intracellular effectors, and associated enzymes further confirming enhanced mRNA stability of Notch1
(Figure 5). In a study by He et al., it was observed that upon METTL14 knockout. Subsequent knockout of
the expression levels of the Notch ligand DLL1 and the Notch1 resulted in a decrease in the sphere-forming
acetylglucosaminyltransferase manic fringe (MFNG) were ability of BCSCs. Notably, further experiments involving
elevated in 67LR /CEACAM6 /CK17 BCSCs. Notably, METTL14 knockout in Notch1 knockout cells led to an
-
41
+
+
glycosylation of Notch receptors 1 – 4 by MFNG facilitated additional decrease in sphere-forming ability, suggesting a
their binding to ligands (DLL1, DLL3, DLL4, JAG1, JAG2), crucial role for Notch1 in the function of METTL14. Thus,
6
thus initiating signal transduction. Interestingly, the high the m A modification regulated by the METTL14-Notch1
expression of Notch1 led to a more than two-fold reduction pathway has been found to control the self-renewal ability
64
in colony formation ability, suggesting a potential anti- of BCSCs, suggesting the variable function of Notch1 in
cancer effect of Notch1 in BC. 41 BCSCs. While excessively high levels of Notch1 may inhibit
the proliferative capacity of BC cells, Notch1 knockout
However, in 2019, researchers led by Chaohui Gu at
Zhengzhou University established T24 cells with Notch1 could suppress the self-renewal of BCSCs.
knockout. Their results revealed that Notch1 knockout Upon binding with its ligand, the Notch receptor
led to a decrease in sphere-forming ability, indicating undergoes two enzymatic cleavage steps to release the
the potential involvement of Notch1 in the self-renewal Notch intracellular domain (NICD), which subsequently
of BCSCs. Furthermore, through RNA dot blot and translocates into the cell nucleus. Notch1 and Notch2,
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immunofluorescence analyses of CD44 BCNSCs and members of the Notch family, usually exhibit pro-cancer
-
CD44 BCSCs isolated from six BC patient samples, they roles, while Notch3 has been shown to enhance the
+
observed a significant decrease in the N6-methyladenosine proliferation, tumorigenicity, and drug resistance of BC
6
(m A) modification level in BCSCs compared to BCNSCs. cells. However, the specific mechanisms underlying these
6
m A modification, known for its role in modifying RNA, effects within the Notch pathway remain unclear. 65
Volume 1 Issue 1 (2024) 33 doi: 10.36922/mi.2377