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Oral Fibrosis and Oral Cancer: From Molecular Targets to Therapeutics

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 48099

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Prof. Dr. Cheng-Chia Yu

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Institute of Oral Sciences, College of Oral Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
Interests: cancer stemness; microRNAs; long non-coding RNAs; oral submucous fibrosis; oral cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Oral submucous fibrosis (OSF) is a chronic scarring disease that has been considered as a pre-cancerous condition of the oral mucosa with a rate of malignant transformation around 7–13%. Therefore, it is imperative to further decipher the mechanism underlying the pathogenesis of OSF and oral cancer in order to develop better treatment approaches and prevent cancer development. To date, it has been known that OSF is associated with the increased myofibroblast activity and dysregulation of collagen homeostasis. As such, inhibition of myofibroblast activation has been regarded as a potential therapeutic direction for OSF. On the other hand, mounting evidence has shown that chemo/radioresistance and metastasis are due to the existence of cancer stem cells or epithelial-mesenchymal transition (EMT). It has been revealed that various non-coding RNAs are key regulators of cancer stemness and EMT and may also be the critical factors that affect the progression of OSF or oral cancer. Moreover, several natural compounds have been shown to exhibit the capacity to modulate the expression of these non-coding RNAs and may serve as promising adjunct therapies to treat OSF or oral cancer.

In this Special Issue, contributions are encouraged to discuss screening strategies, pathogenesis, molecular targets, and therapeutics options for OSF and oral cancer. It is envisioned that this Special Issue will help readers to become more familiar with cutting-edge advances and may even accelerate the discovery and development of effective treatments for OSF and oral cancer.

Prof. Dr. Cheng-Chia Yu
Guest Editor

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Keywords

oral submucous fibrosis
oral Cancer
myofibroblast
epithelial-mesenchymal transition
natural compounds
non-coding RNAs (ncRNAs)
miRNAs
lncRNAs
chemo/radioresistance
metastasis

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Research

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13 pages, 2613 KiB

Open AccessArticle

Targeting lncRNA H19/miR-29b/COL1A1 Axis Impedes Myofibroblast Activities of Precancerous Oral Submucous Fibrosis

by Cheng-Chia Yu, Yi-Wen Liao, Pei-Ling Hsieh and Yu-Chao Chang

Int. J. Mol. Sci. 2021, 22(4), 2216; https://doi.org/10.3390/ijms22042216 - 23 Feb 2021

Cited by 37 | Viewed by 3368

Abstract

Oral submucous fibrosis (OSF) is known as a potentially malignant disorder, which may result from chemical irritation due to areca nuts (such as arecoline). Emerging evidence suggests that fibrogenesis and carcinogenesis are regulated by the interaction of long noncoding RNAs (lncRNAs) and microRNAs. Among these regulators, profibrotic lncRNA H19 has been found to be overexpressed in several fibrosis diseases. Here, we examined the expression of H19 in OSF specimens and its functional role in fibrotic buccal mucosal fibroblasts (fBMFs). Our results indicate that the aberrantly overexpressed H19 contributed to higher myofibroblast activities, such as collagen gel contractility and migration ability. We also demonstrated that H19 interacted with miR-29b, which suppressed the direct binding of miR-29b to the 3′-untranslated region of type I collagen (COL1A1). We showed that ectopic expression of miR-29b ameliorated various myofibroblast phenotypes and the expression of α-smooth muscle actin (α-SMA), COL1A1, and fibronectin (FN1) in fBMFs. In OSF tissues, we found that the expression of miR-29b was downregulated and there was a negative correlation between miR-29b and these fibrosis markers. Lastly, we demonstrate that arecoline stimulated the upregulation of H19 through the transforming growth factor (TGF)-β pathway. Altogether, this study suggests that increased TGF-β secretion following areca nut chewing may induce the upregulation of H19, which serves as a natural sponge for miR-29b and impedes its antifibrotic effects. Full article

(This article belongs to the Special Issue Oral Fibrosis and Oral Cancer: From Molecular Targets to Therapeutics)

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21 pages, 3372 KiB

Open AccessArticle

Adaptation to Endoplasmic Reticulum Stress Enhances Resistance of Oral Cancer Cells to Cisplatin by Up-Regulating Polymerase η and Increasing DNA Repair Efficiency

by Cho-Yi Chen, Masaoki Kawasumi, Tien-Yun Lan, Chi-Lam Poon, Yi-Sian Lin, Pin-Jou Wu, Yao-Chung Chen, Bing-Hong Chen, Cheng-Hsien Wu, Jeng-Fan Lo, Rueyhung Roc Weng, Yi-Chen Sun and Kai-Feng Hung

Int. J. Mol. Sci. 2021, 22(1), 355; https://doi.org/10.3390/ijms22010355 - 31 Dec 2020

Cited by 15 | Viewed by 4237

Abstract

Endoplasmic reticulum (ER) stress response is an adaptive program to cope with cellular stress that disturbs the function and homeostasis of ER, which commonly occurs during cancer progression to late stage. Late-stage cancers, mostly requiring chemotherapy, often develop treatment resistance. Chemoresistance has been linked to ER stress response; however, most of the evidence has come from studies that correlate the expression of stress markers with poor prognosis or demonstrate proapoptosis by the knockdown of stress-responsive genes. Since ER stress in cancers usually persists and is essentially not induced by genetic manipulations, we used low doses of ER stress inducers at levels that allowed cell adaptation to occur in order to investigate the effect of stress response on chemoresistance. We found that prolonged tolerable ER stress promotes mesenchymal–epithelial transition, slows cell-cycle progression, and delays the S-phase exit. Consequently, cisplatin-induced apoptosis was significantly decreased in stress-adapted cells, implying their acquisition of cisplatin resistance. Molecularly, we found that proliferating cell nuclear antigen (PCNA) ubiquitination and the expression of polymerase η, the main polymerase responsible for translesion synthesis across cisplatin-DNA damage, were up-regulated in ER stress-adaptive cells, and their enhanced cisplatin resistance was abrogated by the knockout of polymerase η. We also found that a fraction of p53 in stress-adapted cells was translocated to the nucleus, and that these cells exhibited a significant decline in the level of cisplatin-DNA damage. Consistently, we showed that the nuclear p53 coincided with strong positivity of glucose-related protein 78 (GRP78) on immunostaining of clinical biopsies, and the cisplatin-based chemotherapy was less effective for patients with high levels of ER stress. Taken together, this study uncovers that adaptation to ER stress enhances DNA repair and damage tolerance, with which stressed cells gain resistance to chemotherapeutics. Full article

(This article belongs to the Special Issue Oral Fibrosis and Oral Cancer: From Molecular Targets to Therapeutics)

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13 pages, 2170 KiB

Open AccessArticle

Activation of the miR-371/372/373 miRNA Cluster Enhances Oncogenicity and Drug Resistance in Oral Carcinoma Cells

by Shu-Chun Lin, Hsiao-Li Wu, Li-Yin Yeh, Cheng-Chieh Yang, Shou-Yen Kao and Kuo-Wei Chang

Int. J. Mol. Sci. 2020, 21(24), 9442; https://doi.org/10.3390/ijms21249442 - 11 Dec 2020

Cited by 17 | Viewed by 2772

Abstract

Oral squamous cell carcinoma (OSCC) is among the leading causes of cancer-associated deaths worldwide. Family members in miR-371/372/373 miRNA cluster, which is localized at human chromosome 19q13.4, are co-expressed in both human stem cells and malignancies. The individual miRNA in this cluster are also involved in modulating the pathogenesis of malignancies as either oncogenes or suppressors. The 19q13 region is frequently gained in head and neck cancers. High expression of miR-372 and miR-373 are survival predictors for OSCC. However, the role of the miR-371/372/373 cluster in oral carcinogenesis remains to be fully investigated. We use the clustered, regularly interspaced, short palindromic repeats (CRISPR)-Cas9 system to establish OSCC cell subclones that had the miR-371/372/373 cluster deleted. In addition, further subclones were established that had the promoter of this cluster deleted. Concordant silencing in SAS cells of miR-371/372/373 decreased oncogenic potential, increased cisplatin sensitivity, activated p53, and upregulated the expression of Bad and DKK1. We also employed the CRISPR/dCas9 synergistic activation mediator system, which allowed robust transcriptional activation of the whole miR-371/372/373 cistron. Upregulation of endogenous miR-371/372/372 expression increased both oncogenicity and drug resistance. These were accompanied by a slight activation of AKT, β-catenin, and Src. This study identifies the oncogenic role of the miR-371/372/373 cluster in OSCC. Using CRISPR based strategy can be a powerful paradigm that will provide mechanistic insights into miRNA cluster functionality, which will also likely help the development of targeting options for malignancies. Full article

(This article belongs to the Special Issue Oral Fibrosis and Oral Cancer: From Molecular Targets to Therapeutics)

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12 pages, 7532 KiB

Open AccessArticle

Establishment of a p53 Null Murine Oral Carcinoma Cell Line and the Identification of Genetic Alterations Associated with This Carcinoma

by Kuo-Wei Chang, Chia-En Lin, Hsi-Feng Tu, Hsin-Yao Chung, Yi-Fen Chen and Shu-Chun Lin

Int. J. Mol. Sci. 2020, 21(24), 9354; https://doi.org/10.3390/ijms21249354 - 8 Dec 2020

Cited by 7 | Viewed by 3652

Abstract

Head and neck squamous cell carcinoma (HNSCC), including oral squamous cell carcinoma (OSCC), ranks sixth in cancer incidence worldwide. To generate OSCC cells lines from human or murine tumors, greatly facilitates investigations into OSCC. This study describes the establishing of a mouse palatal carcinoma cell line (designated MPC-1) from a spontaneous tumor present in a heterozygous p53 gene loss C57BL/6 mouse. A MPC-1-GFP cell subclone was then generated by lentivirus infection resulting in stable expression of green fluorescent protein. Assays indicated that MPC-1 was a p53 null polygonal cell that was positive for keratinocyte markers; it also expressed vimentin and showed a loss of E-cadherin expression. Despite that MPC-1 having strong proliferation and colony formation capabilities, the potential for anchorage independent growth and tumorigenesis was almost absent. Like other murine MOC-L and MTCQ cell line series we have previously established, MPC-1 also expresses a range of stemness markers, various oncogenic proteins, and a number of immune checkpoint proteins at high levels. However, the synergistic effects of the CDK4/6 inhibitor palbociclib on other therapeutic drugs were not observed with MPC-1. Whole exon sequencing revealed that there were high rates of non-synonymous mutations in MPC-1 affecting various genes, including Akap9, Arap2, Cdh11, Hjurp, Mroh2a, Muc4, Muc6, Sp110, and Sp140, which are similar to that the mutations present in a panel of chemical carcinogenesis-related murine tongue carcinoma cell lines. Analysis has highlighted the dis-regulation of Akap9, Cdh11, Muc4, Sp110, and Sp140 in human HNSCC as indicated by the TCGA and GEO OSCC databases. Sp140 expression has also been associated with patient survival. This study describes the establishment and characterization of the MPC-1 cell line and this new cell model should help to advance genetic research into oral cancer. Full article

(This article belongs to the Special Issue Oral Fibrosis and Oral Cancer: From Molecular Targets to Therapeutics)

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12 pages, 4809 KiB

Open AccessArticle

LINC00312/YBX1 Axis Regulates Myofibroblast Activities in Oral Submucous Fibrosis

by Chuan-Hang Yu, Chih-Yuan Fang, Cheng-Chia Yu, Pei-Ling Hsieh, Yi-Wen Liao, Lo-Lin Tsai and Pei-Ming Chu

Int. J. Mol. Sci. 2020, 21(8), 2979; https://doi.org/10.3390/ijms21082979 - 23 Apr 2020

Cited by 14 | Viewed by 2960

Abstract

Oral submucous fibrosis (OSF) has been recognized as a precancerous disorder in the oral cavity. Great effort has been made to inhibit the malignant progression of OSF over the past decades, but the cure of this fibrosis disease has not been discovered. In the present study, we found that a long noncoding RNA, LINC00312, was upregulated in OSF tissues, and positively associated with several fibrosis factors, such as α-SMA, type I collagen, and fibronectin. As such, we sought to investigate the role of LINC00312 in OSF progression and identify its interacting factor that mediated oral fibrogenesis. Our results showed that the inhibition of LINC00312 downregulated the myofibroblast activities, including collagen gel contractility, transwell migration, and wound healing, as well as the gene expression of myofibroblast markers. We verified that YBX1 was a downstream factor of LINC00312 and revealed that the downregulation of YBX1 repressed the gene expression of α-SMA and p-Smad2 along with the reduced myofibroblast phenotypes. Most importantly, we demonstrated that the LINC00312-induced myofibroblast activities were reverted by the knockdown of YBX1, suggesting that the LINC00312-mediated myofibroblast transdifferentiation was through YBX1. Collectively, our findings revealed that the LINC00312/ YBX1 axis may serve as a target for the development of therapies against OSF. Full article

(This article belongs to the Special Issue Oral Fibrosis and Oral Cancer: From Molecular Targets to Therapeutics)

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20 pages, 2933 KiB

Open AccessArticle

Overexpression of Platelet-Derived Growth Factor and Its Receptor Are Correlated with Oral Tumorigenesis and Poor Prognosis in Oral Squamous Cell Carcinoma

by Li-Han Lin, Jiun-Sheng Lin, Cheng-Chieh Yang, Hui-Wen Cheng, Kuo-Wei Chang and Chung-Ji Liu

Int. J. Mol. Sci. 2020, 21(7), 2360; https://doi.org/10.3390/ijms21072360 - 29 Mar 2020

Cited by 39 | Viewed by 4037

Abstract

Oral squamous cell carcinoma (OSCC) is a cancerous disease with poor prognosis. According to the statistics, the 5-year survival rate has not improved significantly over the past 20 years. The platelet-derived growth factor (PDGF) and its signaling pathway is a key regulator of angiogenesis and tumorigenesis. High level of PDGF and its receptor (PDGFR) have been reported in several types of malignancies. In this study, we investigated the relationship of the molecular expression levels of PDGF and PDGFR with clinicopathological parameters in OSCC. To this end, we measured the mRNA and protein levels of PDGF and PDGFR by real-time quantitative PCR (qRT-PCR), immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA), respectively. We found positive correlations of the mRNA levels of PDGFA, PDGFB, and PDGFRB with lymph node metastasis and poor overall survival (OS). High expression of PDGF, PDGFRA, and PDGFRB were remarkably associated with lymph node metastasis and poor OS, as determined by immunohistochemistry. Preoperative serum levels of PDGF-AA and PDGF-BB had a positive correlation with preoperative platelet count. Elevated serum levels of PDGF-AA. PDGF-BB, and platelet count correlated with lymph node metastasis and an unfavorable outcome. In multivariate Cox regression analysis, PDGFA mRNA, PDGFB mRNA, PDGFRB mRNA, PDGF immunoexpression, PDGFRB immunoexpression, serum PDGF-AA, serum PDGF-BB, and platelet count emerged as significant independent prognostic factors for OS. In vitro, we found that elevated PDGF promotes colony formation, migration, and invasiveness of SAS and OECM-1 cancer cell lines. Our results suggest that the expression level of serum PDGF has the potential to become a useful diagnostic marker for the prognosis of OSCC. In addition, PDGFR should be considered as a potential therapeutic target for OSCC. Furthermore, research should be undertaken to elucidate the role of PDGF and PDGFR regarding the behavior of tumor cells in OSCC. Full article

(This article belongs to the Special Issue Oral Fibrosis and Oral Cancer: From Molecular Targets to Therapeutics)

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11 pages, 3900 KiB

Open AccessArticle

Arctigenin Reduces Myofibroblast Activities in Oral Submucous Fibrosis by LINC00974 Inhibition

by Ching-Yeh Lin, Pei-Ling Hsieh, Yi-Wen Liao, Chih-Yu Peng, Cheng-Chia Yu and Ming-Yi Lu

Int. J. Mol. Sci. 2019, 20(6), 1328; https://doi.org/10.3390/ijms20061328 - 16 Mar 2019

Cited by 33 | Viewed by 4843

Abstract

Oral submucous fibrosis (OSF) is an oral precancerous condition associated with the habit of areca nut chewing and the TGF-β pathway. Currently, there is no curative treatment to completely heal OSF, and it is imperative to alleviate patients’ symptoms and prevent it from undergoing malignant transformation. Arctigenin, a lignan extracted from Arctium lappa, has been reported to have a variety of pharmacological activities, including anti-fibrosis. In the present study, we examined the effect of arctigenin on the cell proliferation of buccal mucosal fibroblasts (BMFs) and fibrotic BMFs (fBMFs), followed by assessment of myofibroblast activities. We found that arctigenin was able to abolish the arecoline-induced collagen gel contractility, migration, invasion, and wound healing capacities of BMFs and downregulate the myofibroblast characteristics of fBMFs in a dose-dependent manner. Most importantly, the production of TGF-β in fBMFs was reduced after exposure to arctigenin, along with the suppression of p-Smad2, α-smooth muscle actin, and type I collagen A1. In addition, arctigenin was shown to diminish the expression of LINC00974, which has been proven to activate TGF-β/Smad signaling for oral fibrogenesis. Taken together, we demonstrated that arctigenin may act as a suitable adjunct therapy for OSF. Full article

(This article belongs to the Special Issue Oral Fibrosis and Oral Cancer: From Molecular Targets to Therapeutics)

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Review

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22 pages, 1093 KiB

Open AccessReview

Exploration of Feasible Immune Biomarkers for Immune Checkpoint Inhibitors in Head and Neck Squamous Cell Carcinoma Treatment in Real World Clinical Practice

by Hui-Ching Wang, Tsung-Jang Yeh, Leong-Perng Chan, Chin-Mu Hsu and Shih-Feng Cho

Int. J. Mol. Sci. 2020, 21(20), 7621; https://doi.org/10.3390/ijms21207621 - 15 Oct 2020

Cited by 16 | Viewed by 3189

Abstract

Recurrent locally advanced or metastatic head and neck squamous cell carcinoma (HNSCC) is associated with dismal prognosis because of its highly invasive behavior and resistance to conventional intensive chemotherapy. The combination of targeted therapy and conventional chemotherapy has significantly improved clinical outcomes. In recent years, the development of immunotherapies, such as immune checkpoint inhibitors (ICIs), has further increased treatment responses and prolonged survival. However, the limited response rate, risk of immunotherapy-related adverse effects and high cost of immunotherapy make the identification of predictive markers to optimize treatment efficacy a critical issue. Biomarkers are biological molecules that have been widely utilized to predict treatment response to certain treatments and clinical outcomes or to detect disease. An ideal biomarker should exhibit good predictive ability, which can guide healthcare professionals to achieve optimal treatment goals and bring clinical benefit to patients. In this review, we summarized the results of recent and important studies focused on HNSCC ICI immunotherapy and discussed potential biomarkers including their strengths and limitations, aiming to gain more insight into HNSCC immunotherapy in real world clinical practice. Full article

(This article belongs to the Special Issue Oral Fibrosis and Oral Cancer: From Molecular Targets to Therapeutics)

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26 pages, 1985 KiB

Open AccessReview

Targeting Cellular Metabolism Modulates Head and Neck Oncogenesis

by Yi-Ta Hsieh, Yi-Fen Chen, Shu-Chun Lin, Kuo-Wei Chang and Wan-Chun Li

Int. J. Mol. Sci. 2019, 20(16), 3960; https://doi.org/10.3390/ijms20163960 - 14 Aug 2019

Cited by 22 | Viewed by 4472

Abstract

Considering the great energy and biomass demand for cell survival, cancer cells exhibit unique metabolic signatures compared to normal cells. Head and neck squamous cell carcinoma (HNSCC) is one of the most prevalent neoplasms worldwide. Recent findings have shown that environmental challenges, as well as intrinsic metabolic manipulations, could modulate HNSCC experimentally and serve as clinic prognostic indicators, suggesting that a better understanding of dynamic metabolic changes during HNSCC development could be of great benefit for developing adjuvant anti-cancer schemes other than conventional therapies. However, the following questions are still poorly understood: (i) how does metabolic reprogramming occur during HNSCC development? (ii) how does the tumorous milieu contribute to HNSCC tumourigenesis? and (iii) at the molecular level, how do various metabolic cues interact with each other to control the oncogenicity and therapeutic sensitivity of HNSCC? In this review article, the regulatory roles of different metabolic pathways in HNSCC and its microenvironment in controlling the malignancy are therefore discussed in the hope of providing a systemic overview regarding what we knew and how cancer metabolism could be translated for the development of anti-cancer therapeutic reagents. Full article

(This article belongs to the Special Issue Oral Fibrosis and Oral Cancer: From Molecular Targets to Therapeutics)

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22 pages, 833 KiB

Open AccessReview

Oral Submucous Fibrosis: A Review on Etiopathogenesis, Diagnosis, and Therapy

by Yin-Hwa Shih, Tong-Hong Wang, Tzong-Ming Shieh and Yu-Hsin Tseng

Int. J. Mol. Sci. 2019, 20(12), 2940; https://doi.org/10.3390/ijms20122940 - 16 Jun 2019

Cited by 144 | Viewed by 13103

Abstract

Oral submucous fibrosis (OSF) is characterized by abnormal collagen deposition. It is a precancerous disorder and transforms into a malignant tumor in 1.5–15% of all cases. Symptoms include submucous fibrosis, ulceration, xerostomia, a burning sensation, and restricted mouth opening. All of these greatly interfere with patient quality of life. The present review introduces OSF from a molecular perspective and summarizes what is known about its underlying mechanisms, diagnostic biomarkers, and therapeutic interventions. In addition to the aggressive treatment of OSF, its prevention is also important. Future research should, therefore, focus on improving the oral health literacy of the patients susceptible to OSF. Full article

(This article belongs to the Special Issue Oral Fibrosis and Oral Cancer: From Molecular Targets to Therapeutics)

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