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Xu et al. Radiation therapy in keloids treatment

density energy deposition. [34] On the contrary, low- ensued to elucidate the biological significance of the
LET ionizing irradiation technology (X-rays, gamma- aberrant expression of p53 benign soft tissue lesions.
rays and electrons) addresses the indirect actions, As keloids gradually being considered as dysregulated
accomplishing a ratio between indirect and direct wound healing process, a study randomly selected
actions. Both of these actions achieve lethal DNA 20 archival-paraffin-embedded keloid samples for an
damage, comprising single strand DNA breaks, double immunoperoxidase assay with antibodies against fas,
strand DNA breaks and DNA cross-linking. Even p53, bcl-2, and bcl-x using target antigen-retrieval
though most of these damages can be repaired by technique. [43] Among them, 18 of 20 keloids expressed
efficient base repair excision system. A small fraction p53 protein, while bcl-2 was expressed in 19 of 20
of complex DSB, however, was the exception, which fibroblasts, which indicated that focal dysregulation
leads to ultimate cell death. As for cancer cells, of p53 combined with upregulation bcl-2 might help
complexity of mechanisms induced a variety of cell produce a combination of increased cell proliferation
death mentioned above, having many pathways and decreased cell death in keloids. Prominent Fas
assumed. One previous study made use of cancer expression was detected in all 20 specimens, limited
patients’ microarray data prior- or post-irradiative to to the central area, favoring the potential hypothesis
obtain differentially expressed genes, protein domain that p53-induced Fas apoptotic process dysregulated
enrichment analysis also help to highlight some in keloid hyper-proliferative area. Another study in
related pathways. [35] Notably, deemed as the aberrant exploration differences in different regions in entire
wound healing process, collagen synthesis related keloid tissue, the “older parts of the keloid”, the central
genes were also unearthed. The collagen triple helix parts of keloids are shrunken and soft in texture
repeat family members collagen type (COL) 5A2, compared with peripheral keloids tissue parts, showing
COL9A3, COL6A3, COL21A1, COL5A3, COL11A1, much less proliferative and invasive characteristics. [44]
COL7A1 was significantly identified by protein-protein With majority of fibroblasts derived from keloid centers
interaction. Notably, there was no clear evidence staying in G0 or G1 phase, Fas and Bcl-2 expression
explaining the exact mechanisms other than direct did not differ significantly between the two regions, but
damage towards DNA. We not only want to extract p53 expression was much higher in fibroblasts derived
the molecular pathways from closely related research from central parts than from peripheral parts. [45] Based
but also provide insights from keloid formation process on these molecular explanations for cells’ overgrowth in
and cancer cell response towards radiation therapy. keloid tissues, experimental 5-FU modality induced p53
and p21 accumulation together with a decrease in cyclin
P53 and apoptosis B1 and Bcl-2 levels in treated keloid fibroblasts. [46,47]
Even the pathways were not fully elucidated, direct Further evidence uncovered several possible
and indirect DNA damage will be largely repaired by explanations for how p53 played in keloid scarring.
the cell DNA repair system, generating G1/G2/M block. As a sequence-specific transcription repressor of p53,
However, the cellular response and characteristics of overexpression of ΔN63 isoform showed essential
targeted tissue cells are quite complicated. Genomic dominance in suppressing p53 protein in keloid tissues
instability and chromosome aberrations were observed compared to normal skin, with the similar nuclear
in vitro studies by radiation induction apoptosis. Being localization like p53 protein. [48,49] Dysregulated p53
the principle guardian of DNA damage response, p53 function, altered expression and asymmetric protein
accordingly maintains the genetic stability through deposition observed in keloid tissues all enables
phosphorylated ATM or phosphorylated ATR proteins. [36] its potential as the main target. Both contribution to
ATM-p53-Bax-cytochrome C was reportedly intrinsic and extrinsic apoptotic pathway, reactivation,
associated with apoptosis, while the p53-Capspases- upregulation and accumulation of p53 in response to
cytochrome c pathway mitotic catastrophe-related. [37,38] ionizing irradiation initiated the caspase lethal pathway,
What’s more, p53 also enabled extrinsic CD95-FADD- achieving programmed cell death.
caspases apoptotic pathway, which is considered to be
enhanced by CD-95 mediated pathway. [34] Senescence TGF-β and response to irradiation
was also believed to have p53 regulation involved. [39] TGF-β was considered as the major altered pathway
Dysregulated p53 expression and function plays a explained in keloids’ pathogenesis, especially at early
critical role in tumorigenesis of diversified malignant stages. [50] More than 90% immunostaining in keloids
tumors. Abnormal expression of p53 in non-neoplastic was significantly higher than the 60% found in normal
lesions and benign neoplasmas of soft tissue including scars. Significant elevation of TGF-β expression was
keloids was also brought to light early in 1993, positivity observed in keloid tissue compared to normal tissue,
in 9 of 9 keloids tissues baffling researchers whether which may be explained by alteration expression
it indicated malignancy. [40-42] Further genetic studies of SMAD3, SMAD6 and SMAD7. [51] Specifically,
120 Plastic and Aesthetic Research ¦ Volume 4 ¦ July 28, 2017