Distribution pattern of invasion‑related bio‑markers in head Marjolin's ulcer

  • Authors:
    • Zhihui Ni
    • Zhao Zheng
    • Enxing Yu
    • Can Zu
    • Dongdong Huang
    • Ke Wu
    • Jiangnan Hu
    • Sheng Ye
    • Qichuan Zhuge
    • Jianjing Yang
    • Linhui Ruan
  • View Affiliations

  • Published online on: July 23, 2020     https://doi.org/10.3892/etm.2020.9034
  • Pages: 3316-3323
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Abstract

Marjolin's ulcer (MU) is a rare and aggressive cutaneous malignancy that typically presented in an area of traumatized or chronically inflamed skin and particularly in burn scars. Among them, the MU in the scalp with extensive invasion of the skull is exceptional and severe. The principle of management for MU is to obtain an early diagnosis and perform prompt surgical interventions. The invasive capacity of MU may vary among different sites of the scalp, which may require different therapeutic strategies for surgical excision. However, no clear evidence has been provided to determine the invasion ability of MU at different regions of the lesion as a surgical guidance. In present study, a 41‑year‑old female with a 40‑year history of scalp ulceration has been examined. After resection of the MU lesion, hematoxylin and eosin (H&E) staining was performed to confirm the pathology of the cutaneous malignancy after surgical excision. Furthermore, reverse transcription‑quantitative PCR experiment was performed out to determine the expression levels of invasion‑associated biomarkers at different sites of the scalp affected by MU. Pathological analysis with H&E staining indicated a differentiated squamous cell carcinoma with invasion of the skull. The invasion‑associated biomarkers were highly expressed in the core region compared to the middle region as well as the edge of MU tissue. Taken together, the present study suggests that the expression pattern of invasion‑associated biomarkers varies between different regions of the MU lesion. High expression levels in the core region of MU indicates that the resection of the center area may be critical for the successful surgical treatment of MU.

Introduction

Marjolin's ulcer (MU) is a rare and aggressive cutaneous malignancy that typically develops in an area of traumatized or chronically inflamed skin, particularly in burn scars (1,2). The incidence of burn scars undergoing malignant transformation is approximately 0.77% ~ 2% (3). Squamous cell carcinoma (SCC) is the most common pathologic type of MU (4). However, compared to conventional skin SCC, MU tends to be more aggressive. In 1828, Marjolin reported a case of malignant ulcer secondary to burn scar and the term ‘Marjolin's ulcer’ has then been applied to describe malignant tumors occurring in post-traumatic scars (5). MU usually occurs on the extremities, the joints, or other regions of the body that have a high level of mobility, and MU on the head has been rarely reported. Lesions of MU on the head are mainly include burn scar carcinomas of the scalp and are capable of skull bone destruction (6). When MU cells invade the skull, affected patients have a higher risk of higher morbidity rate and a worse outcome (7). In order to suppress invasion of the skull and potentially the brain tissue, expeditious and wide excision of MU lesions at early time-point is necessary and should be the principle of surgical treatment. Furthermore, elucidation of the invasion ability in different regions of the tumor may help develop a proper strategy for surgical resection and comprehensive management. In solid epithelial cancer, the invasion ability of tumor cells is a crucial requirement for cancer progression, which appears to be the most complex and least understood process. Previous studies have indicated that numerous have showed that many factors and signaling pathways are involved in the dynamic invasion process of cancer cells (8). The important initial step is the separation of tumor cells from the adjacent stroma to progress to the early stages of cancer formation (9). Due to the reduction of cell-to-cell adhesion and acquisition of invasive capabilities by epithelial-mesenchymal transition (EMT), tumor cells may transmigrate through the basement membrane (10). During the EMT process, cancer cells may become even more separated from each other due to the abnormal regulation of cell adhesion molecules (e.g., E-cadherin, claudin, and desmoglein). Furthermore, EMT allows tumor cells to undergo multiple biochemical transformations which strengthen their ability to invade and migrate, as well as marked increases in the production of extracellular matrix matrices (ECM) components. This creates a favorable tumor microenvironment (TME) for the surrounding cancer cells (11). More specifically, TME has a vital role in tumorigenesis and particularly in tumor invasion. Certain molecules in TME, including matrix metalloproteinase (MMP)-2, MMP-9, MMP-14 and periostin) promote the invasiveness of cancer cells. In addition, errors occurring in the cell signaling interactions and cellular information processing may also be responsible for the diseases including such as cancer, as cell signaling is a part of any communication process which governs basic activities of cells and coordinates all cell actions (8). For instance, the receptor activator of NFκΒ (RANK), epidermal growth factor receptor (EGFR), STAT and focal adhesion kinase (FAK) cell signaling pathways are involved in the initiation and maintenance of the cutaneous invasion process.

The principle of management of MU is to obtain an early diagnosis and perform prompt surgical interventions. The invasion ability of MU may vary among different sites of the scalp, which may require different therapeutic strategies for surgical excision. However, no clear evidence has been provided to indicate the various invasion abilities of MU at different regions that may be used for surgical guidance. Cell adhesion molecules, the TME and cell signaling pathways are the major components that may have significant roles in burn scar carcinogenesis post burn, and also the progression of MU. In the present study, MU scalp samples were collected from the different lesion sites (core, middle and edge regions), and a comprehensive analysis was performed to detect the expression levels of invasion-associated biomarkers in those areas, including cell adhesion molecules, expression of TME-associated genes and cell signaling pathway components. Of note, the expression of biomarkers of the tumor invasiveness was different among various sites of the scalp affected by MU. Of note, high expression levels of certain biomarkers were detected in the core region of MU compared to the middle and edge areas. These results may provide information for developing appropriate therapeutic strategies of the MU treatment in the future.

Patients and methods

Patients and samples

Tissue samples, including one MU and three normal scalp samples were obtained from surgical specimens of patients at the Department of Neurosurgery, the First Affiliated Hospital of Wenzhou Medical University, China. Informed consent was obtained from all patients. For acquiring the MU tissue in different site, during the surgery, a total of nine tissue samples were obtained from three different sites of the MU tumor (3 from the core, 3 from the middle and 3 from the edge) (Fig. 1E). The other three normal scalp samples were acquired during scalp mass resection. The general information of the patient was listed in the Table I. The tissue samples were preserved immediately after excision.

Table I

Demographic characteristics of patients.

Table I

Demographic characteristics of patients.

Patient no.SexAgeLocalizationHistopathological typeSample name
1Female41Parietal regionSquamous cell carcinomaMU tissue
2Female51Right occipital regionEpidermoid cystNormal tissue
3Male36Right frontal regionLiomyomaNormal tissue
4Female38Left parietal regionRoot sheath cystNormal tissue

[i] MU, Marjolin's ulcer.

Hematoxylin and eosin (H&E) staining

The patients' tissues were preserved in 10% formalin and embedded in paraffin sections. In a routine procedure, the sections were prepared and stained with H&E (12,13). A Leica DMI4000B microscope (Leica Microsystems) was used for the image capture.

mRNA isolation and reverse transcription-quantitative (RT-q)PCR

Total RNA of each sample was isolated from MU tissues and normal scalp samples by using TRIzol reagent (Tiangen Biotech Co., Ltd., Beijing, China) according to the manufacturer's instructions. RNA quantity and quality were measured using a NanoDrop ND-1000 (Thermo Fisher Scientific, Inc.). RNA samples were stored at -80˚C until further use. Approximately 2 µg of total RNA was converted to the first-strand cDNA using a SuperScript II RT system (Tiangen Biotech). qPCR was performed in a 20 µl reaction volume in the presence of SYBR® Fast qPCR Mix (Takara Biotechnology, Co., Ltd.) on an ABI Q5 Real-Time PCR (Thermo Fisher Scientific, Inc.) according to the manufacturer's protocols. The primers used are listed in Table II. The reactions were performed in triplicate and results were expressed as the ratio of the quantification cycle (Cq) value for the cDNA concentration of the target gene with normalization to GAPDH using the 2-ΔΔCq method (14).

Table II

Primer list for reverse transcription-quantitative PCR.

Table II

Primer list for reverse transcription-quantitative PCR.

Gene nameForward primer (5'-3')Reverse primer
Periostin ACAAGAAGAGGTCACCAAGGTC TTGGCTTGCAACTTCCTCAC
MMP-14 GAGCATTCCAGTGACCCCTC ACCCTGACTCACCCCCATAA
MMP-2 GGCGCGCTCACGGGT TCAGGTATTGCACTGCCAACT
MMP-9 CGCGCTGGGCTTAGATCATT GTTCAGGGCGAGGACCATAG
Claudin-1 CCAGTCAATGCCAGGTACGA GGCCTTGGTGTTGGGTAAGA
Desmoglein-3 AGTGCCTCAAACTCACTGGT ACGGACTTCCCCAGTGTTTC
E-cadherin ATGCTGATGCCCCCAATACC GCTGCTTGGCCTCAAAATCC
RANKL GTACCAGGGATGTGACGTGG TCAGGTGATCTCTCATTCTTTTCT
FAK TCAAGCCATGGAGGCTTCAG GGGGCTGGCTGGATTTTACT
STAT3 GAAACAGTTGGGACCCCTGA CTCTCAATCCAAGGGGCCAG
EGFR TATTGATCGGGAGAGCCGGA TCGTGCCTTGGCAAACTTTC
CXCL9 TGATTGGAGTGCAAGGAACCC AAGGGCTTGGGGCAAATTGT
GAPDH CAGGAGGCATTGCTGATGAT GAAGGCTGGGGCTCATTT

[i] MMP, MMP, matrix metalloproteinase; RANKL, receptor activator of NFκΒ ligand; EGFR, epidermal growth factor receptor.

Western blot analysis

Firstly, the different tissue samples were lysed with RIPA lysis, which contain phosphatase inhibitors and protease inhibitor (Thermo Fisher Scientific, Inc.). After centrifuged at 12,000 rpm for 30 min, we collected the supernatant. The concentration of protein was anlyzed by Pierce bicinchoninic acid assay (BCA) protein assay kit (Thermo Fisher Scientific, Inc.). Proteins from tissue were separated in 15% SDS-PAGE and then transferred to a polyvinylidene difluoride (PVDF) filter membranes (Millipore). After blocked with 3% BSA (BioFroxx) for 2 h, the PVDF membranes were incubated at 4˚C overnight with primary antibodies against p-STAT3 (Rabbit Polyclonal, CST, #9145 1:1,000), p-EGFR (Rabbit Polyclonal, Affinity Biosciences, #AF3048, 1:1,000), p-FAK (Rabbit Polyclonal, Affinity Biosciences, #AF3398, 1:1,000) and β-actin (Rabbit Polyclonal, Abcam, ab8227, 1:1,000). PVDF membranes were washed in TBST before incubated with secondary antibody (1:5,000) for 1h at RT. The membrane were washed with PBST and then visualization by ECL HRP substrate (Advansta).

Statistical analysis

Values are expressed as the mean ± standard error of the mean. GraphPad PRISM software (version 7, GraphPad Software, Inc.) was used for the statistical data analysis. The One-way ANOVA followed by Bonferroni's Multiple Comparison was performed to determine the statistical significance of the RT-qPCR results results. P<0.05 was considered to indicate a statistically significant difference.

Results

Case report

A 41-year-old female presented with a 40-year history of scalp ulceration presented at our department. As the disease progressed, she started to experience repeated bleeding in the ulceration lesion site for about ~1 year. The patient was reported to have contracted a burn scar from fires in the parietal region of the scalp at the age of one. In the beginning, the size of the scar was close to that of a broad bean. The ulceration of the scalp gradually increased over decades and was accompanied with a mild itching and it eventually developed into a lesion with repeated bleeding one year prior to presentation. When the patient was admitted, the size of the scalp ulcers was ~8x8 cm2 (Fig. 1A). A CT scan demonstrated the parietal bone destruction with a huge mass on top of the skull (Fig. 1C). MRI sagittal images revealed invasion of the parietal bone by the tumor tissue with the size of about ~18x9 mm2 (Fig. 1B). A surgical operation was performed to excise the scalp ulceration and remove the affected parietal bone. The scalp ulceration was excised by leaving 1 cm of security skin margin around the scar tissue. The diseased parietal bone was resected, and the wound was reconstructed with an autologous skin flap (Fig. 1D). During the surgery, a total of nine tissue samples were obtained from three different sites of the MU tumor for further analysis (3 from the core, 3 from the middle and 3 from the edge) (Fig. 1E).

Pathological analysis of MU tissue.

H&E staining was performed to pathologically analyze the MU. The MU was pathologically classified as poorly differentiated SCC (Fig. 2A) associated with skull bone invasion (Fig. 2B). After extended resection of MU lesion tissue, the residual surrounding tissue (1 cm tumor-free margin) was confirmed as the normal scalp tissue via H&E staining (Fig. 2C and D).

Distribution of invasion-associated cell adhesion molecules at different sites of MU

To validate the hypothesis that the invasive ability of tumor cells may vary among different regions of the MU, the RT-qPCR analysis was performed to detect the expression levels of the selected cell adhesion-associated molecules in different parts of the MU (core, middle, and edge sites) and the normal skin. The RT-qPCR results revealed that the expression of claudin-1, desmoglein-3 and E-cadherin in MU was significantly higher compared with that in normal scalp tissue (Fig. 3). Furthermore, the expression levels of claudin-1 and desmoglein-3 in MU (edge) were significantly increased compared with those in MU middle). However, there was no significant difference in E-cadherin expression at the locations between MU (edge) and MU (middle). Of note, claudin-1 and desmoglein-3 exhibited the highest expression levels in the MU (core) samples compared with those in the samples from others parts, while E-cadherin had the lowest expression level in the core region among all samples (Fig. 3).

TME-associated gene expression at different sites of MU

According to current concepts of tumor biology, the TME is crucial for tumor cell growth. To evaluate the TME conditions at the different sites of MU, RT-qPCR analysis was performed to detect the expression levels of TME-associated biomarkers (MMP-2, MMP-9, MMP-14 and periostin). Compared with those in the normal control group, the expression of all selected TME-associated biomarkers in MU was significantly promoted. Of note, the core region of the MU lesion exhibited tissue shows the highest expression levels of MMP-2, MMP-9, MMP-14 and periostin compared to the others (Fig. 4).

Expression of tumor invasion-associated cell signaling molecules at different sites of MU

Certain cell signaling pathways are involved in the cutaneous invasion process. These representative molecular biomarkers were clearly detected by RT-qPCR experiment in the biopsy samples from the MU lesion sites, including FAK, STAT3, EGFR, C-X-C motif chemokine ligand (CXCL)9 and RANK ligand (RANKL). Of note, along with the TME-associated molecules, all of those selected molecules were significantly overexpressed in MU (Core) samples compared to the samples from the other sites. In addition, the expression levels of all of the selected molecules in MU tissues were higher than those in the normal skin tissue (Fig. 5A-E). Furthermore, Western blot experiment has been performed to determine the level of phosphorylated STAT3, FAK and EGFR. The results also indicted that all of those phosphorylation molecules were significantly increased in MU (Core) samples compared to the samples from the other sites (Fig. 5F-I).

Discussion

MU is a rare and aggressive malignancy disease with an ominous prognosis, particularly head MU (2). Understanding the exact pathogenesis of MU may markedly enhance the effectiveness of the treatment. Due to the invasion ability of MU, the principle of wide resection of MU is critical for successful surgical treatment. In the present study, it was revealed that the various regions of a scalp MU exhibit differential invasiveness based on the expression of invasion-associated genes, which provides some insights for the surgical treatment of MU. It may be concluded that the core part of MU had invasion properties, particularly in skull invasion, which should receive sufficient attention during clinical therapy.

The acquirement of invasive properties and ability to form metastasis are a key hallmark of cancer progression. In the present, we disclosed the expression levels of several different invasion-associated biomarkers were assessed at different sites of MU, including cell adhesion-associated molecules, TME-associated molecules and certain molecules which involved in invasion-associated cell signaling pathways (8). Sinha et al reported that acquisition of epithelial-to-mesenchymal transition (EMT) may underlie the high metastatic rate in MU tumors (15). The abnormal expression of cell adhesion molecules is in accordance with the invasion of SCC, including claudin-1, E-cadherin and desmoglein (DSG), which represents the tumor progression ability (16). Among these, claudin-1 is well known as a key factor, which has a major role in tight junction signaling (17,18). Functional alterations of tight junctions have been widely indicated in various types of cancers, and are closely linked related to the invasive ability of tumor cells. In addition, E-cadherin reduction is also relevant to epithelial-mesenchymal transition (EMT), which is a crucial process in cancer progression (19). Futhermore, studies have reported that desmoglein is also a molecular which highly expressed in SCC (20). In the present study, based on the analysis of the mRNA expression levels of cell adhesion molecules at different sites of MU, it was evidenced that the core site of MU had the strongest invasive properties.

In addition, several TME-associated genes (MMP-2, MMP-9, MMP-14 and periostin) also have also been selected to explore the tumor microenvironment conditions of MU (21-23). As is known, degradation of restrictive ECM proteins is regulated by matrix metalloproteinases (MMPs), which have a critical role in tumor progression regarding the invasion ability of cancer cells (24). A body of evidence has indicated that the expression of MMPs was markedly elevated in SCC (25,26). In line with this the present study also identified that the expression of MMP-2, MMP-9 and MMP-14 was obviously increased in MU tissue compared with that in the normal skin tissue. Furthermore, the core site of MU tissue exhibited the highest expression of MMPs among all of the tested samples, which indicated that the utmost ability of ECM degradation at that site. In addition, it was demonstrated that periostin as a component of the ECM, was also overexpressed in SCC (27,28). In accordance with these studies, the present results also indicate that the expression of periostin in MU's tissue is higher than that in normal tissue. The core site of the MU exhibited the highest expression levels of periostin among the different sites of the MU. In summary, the microenvironment of the core site of the MU lesion may have features of invasive tumor growth.

In addition to cell adhesion molecules and the TME, several tumor invasion-associated cell signaling molecules were also investigated in the present, including RANK/RANKL, FAK, STAT3, EGFR and CLCX9(8). As is known, RANK/RANKL signaling is critical for osteoclastogenesis, which is an essential element that contributing to bone invasion caused by the tumor cells (29,30). The present results suggested that the expression of RANKL at the core site of MU was increased, which is in compliance with the biological function of the RANK/RANKL signaling pathway in SCC (31). Recent studies have demonstrated that FAK has multiple function in carcinogenesis, particularly in cell proliferation, cell motility, invasion, inhibition of apoptosis, angiogenesis, and immunosuppression (32-34). To discover the possible role of FAK in the present study, RT-qPCR analysis was performed, revealing that the expression level of FAK was the highest in the core region of MU tissue. Furthermore, STAT3, EGFR and CLCX9, as the essential components for invasion and metastasis, were also highly expressed in SCC (35-39). This phenomenon was also observed in the present study by demonstrating higher RNA expression level of STAT3, EGFR and CLCX9 in MU compared with that in the normal skin tissue. Except RNA expression level analysis, western blot experiment also has been used to determine the protein level of phosphorylated STAT3, FAK and EGFR. The results also indicted that all of those phosphorylation molecules were significantly increased in MU (Core) samples compared to the samples from the other sites. However, we do not have paraffin tissue section for Immunohistochemistry (IHC) analysis, which should be also important for protein expression level distribution analysis, is a main limitation in our study. Based on our results, we can conclude that the highest expression level of these biomarkers was present at the center of the MU lesion, indicating that the tumor cells in the center were more aggressive compared with those in surrounding areas.

In conclusion, the present study explored the distribution pattern of the invasion-associated biomarkers at the different sites of a head MU lesion. The results indicated that the expression levels of those invasion-associated genes at different sites of MU exhibited significant differences. The core region of MU exhibited the highest expression level, suggesting the strongest invasion ability. Of note, the present study supports that the resection of the core region and surrounding skull bone is critical for successful surgical interventions of scalp MU which may feature with skull bone invasion. The present study provides a novel and effective strategy for surgical therapy for MU. It may be proposed that the invasion-associated biomarkers at the different sites of the lesion tissue should be suggestively evaluated prior to surgery for the purpose of improving the efficacy and accuracy of MU lesion excision procedures.

Acknowledgements

Not applicable.

Funding

The present study was supported by the National Natural Science Foundation of China (grant no. 81771262), Zhejiang Health Science and Technology Project (grant no. 2016RCA022) and the Zhejiang Key Research and Development Project (grant no. 2017C03027).

Availability of data and materials

All data generated or analyzed during this study are included in the published article.

Authors' contributions

ZN, ZZ, EY, DH, CZ, KW, JY and LR designed and performed the experiments, as well as analyzed and interpreted the data. ZN, KW, JH and SY wrote and edited the manuscript. QZ, SY, JY and LR supervised the project and provided critical input. All authors gave feedback and agreed on the final version of the manuscript.

Ethics approval and consent to participate

All experiments performed in accordance with the institutional guidelines for patient's sample research and approved by the First Affiliated Hospital of Wenzhou Medical University (China).

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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October-2020
Volume 20 Issue 4

Print ISSN: 1792-0981
Online ISSN:1792-1015

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Copy and paste a formatted citation
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Spandidos Publications style
Ni Z, Zheng Z, Yu E, Zu C, Huang D, Wu K, Hu J, Ye S, Zhuge Q, Yang J, Yang J, et al: Distribution pattern of invasion‑related bio‑markers in head Marjolin's ulcer. Exp Ther Med 20: 3316-3323, 2020
APA
Ni, Z., Zheng, Z., Yu, E., Zu, C., Huang, D., Wu, K. ... Ruan, L. (2020). Distribution pattern of invasion‑related bio‑markers in head Marjolin's ulcer. Experimental and Therapeutic Medicine, 20, 3316-3323. https://doi.org/10.3892/etm.2020.9034
MLA
Ni, Z., Zheng, Z., Yu, E., Zu, C., Huang, D., Wu, K., Hu, J., Ye, S., Zhuge, Q., Yang, J., Ruan, L."Distribution pattern of invasion‑related bio‑markers in head Marjolin's ulcer". Experimental and Therapeutic Medicine 20.4 (2020): 3316-3323.
Chicago
Ni, Z., Zheng, Z., Yu, E., Zu, C., Huang, D., Wu, K., Hu, J., Ye, S., Zhuge, Q., Yang, J., Ruan, L."Distribution pattern of invasion‑related bio‑markers in head Marjolin's ulcer". Experimental and Therapeutic Medicine 20, no. 4 (2020): 3316-3323. https://doi.org/10.3892/etm.2020.9034