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Gene & Protein in Disease Perineural invasion in prostate cancer

In the present study, we analyzed the expression of and ROBO2 proteins have been reported to inhibit
genes associated with the hallmark of cancer. Decreased migration of Schwann cells. 44-46 In the present study, we
E-cadherin protein expression after contact of Schwann observed that ROBO1 mRNA levels were increased in
cells with the tumor also occurs during axonal repair perineural invasion-negative prostate cancer samples
process. The loss of E-cadherin during the epithelial– when compared to normal tissue.
mesenchymal transition in cancer is associated with a Since circadian entrainment is an upregulated pathway
positive regulation of NCAM1 and CDH2. 31,35-37 When in perineural prostate-positive tumors, we associated
E-cadherin is suppressed, NCAM1 and CDH2 are DEGs to clock-related gene list. The expression of PER3,
upregulated; they associate with the p59fyn protein, whose NR3C1, PPARGC1A, TIMP3, ID2, PDE6B, SLC25A10, and
subsequent activation leads to inhibition of focal adhesion CAVIN1 was upregulated in perineural invasion-negative
and an increase in cell migration. A study using oncogenic
K-RAS pancreatic cancer cell lines identified increased tumors. We also detected a set of genes upregulated in
levels of polysialylated NCAM1 expression, which interacts perineural invasion-positive invasion, such as PPARGC1A,
with E-cadherin to create steric hindrance of homophilic TIMP3, S100A8, ID2, DEFB1, AQP3, ASS1, PDE6B, NEFH,
binding and decrease cell adhesion. In our study, we and CAVIN1. AQP3 and NEFH (oncogenic clock-related
observed upregulation of NCAM1 in both perineural genes) were upregulated only in perineural invasion-
invasion-negative and -positive cancers. 38,39 positive tumors, while PER3, SLC25A10, and NR3C1
(tumor suppressor clock-related genes) were upregulated
Differentiation of myelinating Schwann cells may only in perineural invasion-negative samples. Previous
undergo interference from inhibitory pathways that studies found that circadian rhythm and melatonin are
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negatively control the expression of genes responsible associated with nerve regeneration. Acting an important
for myelin sheath formation. NOTCH1 and JUN stand mediator of circadian rhythm, melatonin is involved
out among the negative regulators of the myelination in the dedifferentiation and increased proliferation of
pathway, similar to SOX-2 and PAX-3. 9,18,34 The Schwann cells. Although the related mechanism is not
myelinating phenotype also involves the inactivation of fully understood, it has been demonstrated that Ras/Raf/
a number of genes linked to the production of immature ERK, MAPK, and GDNF/PKC pathways can be activated
Schwann cell markers. Some transcription factors are through MIT1/MIT2 receptors, whereas the melatonin can
responsible for ensuring proper maturation in Schwann increase Schwann cell proliferation, causing a heightened
cells. SOX-10 acts synergistically with a second factor, interaction of these cells with cancer cells that leads to
OCT-6, resulting in the expression of KROX-20. In turn, perineural invasion and worse prognosis in prostate
KROX-20 is a key inducer of expression of myelin genes, cancer. We also observed a correlation between AKT
36
such as MBP, MPZ, and PRX. The maintenance of the and MAPK phosphorylation in PRAD samples. Taken
myelinating phenotype, therefore, requires the continuous together, these findings show that circadian rhythm and/
expression of KROX-20 and SOX-10, considering that or melatonin disruption are linked to Schwann cells
inactivation of both proteins results in dedifferentiation of dedifferentiation, which leads to perineural invasion in
Schwann cells. 17,18,40,41 prostate cancer.
Previous studies have shown that Schwann cells
induce cellular aggressiveness in prostate cancer. During 5. Conclusion
dedifferentiation, Schwann cells express proteins initially Axon guidance pathway is upregulated in perineural
lost during the myelination process. Among these invasion-negative prostate cancers. Together with
proteins are GAP43, NCAM1, P75ntr (NGFR), GFAP, an upregulation of the axon guidance pathway, the
and SOX-2. 10,19 Data from our study showed that Ngfr1 upregulation of ROBO1 and MPZ genes, which are
gene expression is increased in both perineural invasion- associated with inhibition of Schwann cells migration,
negative and -positive prostate cancers. It is likely that suppresses perineural invasion pathways. Besides,
Schwann cells in these tissues are dedifferentiated, aiding deregulation of clock-related genes is also an important
tumors in their mechanisms of cell proliferation, migration, molecular feature in patients with perineural invasion-
and tissue invasion. positive prostate cancer. Our findings also revealed that
During the process of carcinogenesis, the SLIT2, dedifferentiation and proliferation of Schwann cells are
ROBO1, and ROBO2, which are regarded as tumor induced by circadian entrainment disruption, leading to
suppressor genes, are inactivated. 42,43 These genes play the production of different factors by the Schwann cells
extremely important roles during the process of nerve driving tumor progression and tumor invasion into the
formation and repair. Furthermore, the SLIT2, ROBO1, perineural tissue in context of prostate cancer.

Volume 3 Issue 3 (2024) 9 doi: 10.36922/gpd.3146