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H& E staining and dual immunostaining findings; A, E Well differentiated SCC (× 100 magnification, 200 μm scale bar). C, G Poorly differentiated SCC (× 100 magnification, 200 µm scale bar). B Low co-expression of CD105 and OCT3/4 in well differentiated SCC; Positive red cytoplasmic immunostaining for CD105 and brown nuclear immunostaining for OCT3/4 in tumoral cells (× 400 magnification, 30 µm scale bar). D High co-expression of CD105 and OCT3/4 in poorly differentiated SCC; Positive red cytoplasmic immunostaining for CD105 and brown nuclear immunostaining for OCT3/4 in tumoral cells (× 400 magnification, 30 µm scale bar). F Low co-expression of GLUT1 and OCT3/4 in well differentiated SCC; Positive red cytoplasmic immunostaining for GLUT1 and brown nuclear immunostaining for OCT3/4 (× 400 magnification, 30 µm scale bar). H High co-expression of GLUT1 and OCT3/4 in poorly differentiated SCC; Positive red cytoplasmic immunostaining for GLUT1 and brown nuclear immunostaining for OCT3/4 (× 400 magnification, 30 µm scale bar)
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Background
Oral squamous cell carcinoma (OSCC) is the most common cancer affecting the oral and maxillofacial region. This study aimed to investigate the role of cancer stem cells (CSCs) in angiogenesis and hypoxic response in OSCC.
Methods
This retrospective observational study evaluated 56 cases of OSCC using dual immunohistochemistry. Octamer-b...
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Citations
... The critical role of the TFs, HIF1α, AP1, and NFκB in tumor progression and chemoresistance of OSCC has been reported (Alam et al., 2017;Alam & Mishra, 2021;Yedida et al., 2013). Besides this, the regulation of GLUT1/3 by OCT3/4 (Derakhshan et al., 2022;Samardzija et al., 2016), ATF2 (Song et al., 2022), TWIST1 (Pehlivanoglu et al., 2021), CREB (Li et al., 2021), and Yin Yang 1 are also evident in the literature. ...
Objective:
This study aimed to determine whether glucose transporter-1/3 (GLUT1/3) increased expression could contribute to oral tumor severity. Furthermore, this study detected whether GLUT1/3 mRNA/protein was associated with oncogenic transcription factors (HIF1α, AP1 and NFκB) and whether by blocking GLUT1 along with cisplatin could sensitize drug-resistant OSCC cells.
Design:
We used 120 post-operated human tissue samples, including 35 primary tumors (PT), 43 invasive tumors (N1-3), 17 recurrent chemoradiation-resistant tumors (RCRT), and 25 PT-adjacent normal tissues (AN). The cisplatin-resistant (CisR-SCC4/9) cells were generated using a drug escalation strategy from parental SCC4/9 cells. The BAY-876 treatment blocked GLUT1 in OSCC cells. Western Blot, Immunohistochemistry, and reverse transcription polymerase chain reaction (RT-PCR) were used to detect various proteins and mRNA. Cell survival was determined by MTT assay.
Results:
GLUT1/3 expression was observed more in PT over AN tissue (PT > AN), N1-3 > PT, and .RCRT > PT. GLUT1 expression was maximum in the RCRT group and CisR-SCC4/9 cells over their parental counterpart, linked with tumor size (p=0.0037) and loco-regional invasiveness (p=0.0422). GLUT1/3 mRNA/protein was correlated (positively) with oncogenic transcription factors (TFs) like HIF1α, AP1 and NFκB. We found the degree of positive correlation of these TFs with GLUT1/3 was in the order c-Jun > HIF1α > Fra-2 > NFκB > c-Fos. Treatment of BAY-876 and cisplatin-induced cell death in both CisR-SCC4/9 cells, possibly by triggering apoptosis and autophagy.
Conclusion:
Collectively, our results demonstrated increased GLUT1/3 overexpression linked with oral tumor severity like invasion and therapy resistance, and it was powered mainly by c-Jun (AP1). Blocking GLUT1 receptors and cisplatin application can sensitize CisR-OSCC cells.
The clinical management of oral cancer is often frequented with challenges that arise from relapse, recurrence, invasion and resistance towards the cornerstone chemo and radiation therapies. The recent conceptual advancement in oncology has substantiated the role of cancer stem cells (CSC) as a predominant player of these intricacies. CSC are a sub-group of tumor population with inherent adroitness to self-renew with high plasticity. During tumor evolution, the structural and functional reprogramming persuades the cancer cells to acquire stem-cell like properties, thus presenting them with higher survival abilities and treatment resistance. An appraisal on key features that govern the stemness is of prime importance to confront the current challenges encountered in oral cancer. The nurturing niche of CSC for maintaining its stemness characteristics is thought to be modulated by complex multi-layered components encompassing neoplastic cells, extracellular matrix, acellular components, circulatory vessels, various cascading signaling molecules and stromal cells. This review focuses on recapitulating both intrinsic and extrinsic mechanisms that impart the stemness. There are contemplating evidences that demonstrate the role of transcription factors (TF) in sustaining the neoplastic stem cell’s pluripotency and plasticity alongside the miRNA in regulation of crucial genes involved in the transformation of normal oral mucosa to malignancy. This review illustrates the interplay between miRNA and various known TF of oral cancer such as c-Myc, SOX, STAT, NANOG and OCT in orchestrating the stemness and resistance features. Further, the cross-talks involved in tumor micro-environment inclusive of cytokines, macrophages, extra cellular matrix, angiogenesis leading pathways and influential factors of hypoxia on tumorigenesis and CSC survival have been elucidated. Finally, external factorial influence of oral microbiome gained due to the dysbiosis is also emphasized. There are growing confirmations of the possible roles of microbiomes in the progression of oral cancer. Given this, an attempt has been made to explore the potential links including EMT and signaling pathways towards resistance and stemness. This review provides a spectrum of understanding on stemness and progression of oral cancers at various regulatory levels along with their current therapeutic knowledge. These mechanisms could be exploited for future research to expand potential treatment strategies.
Intracellular markers of cancer stem cells (CSCs), e.g., ALDH1, SOX2, Oct-3/4, Bmi1, LETM1, Msi2, and Sall4 have a significant role in the isolation and detection of CSC, and these intracellular markers are associated with the diagnosis and prognosis of patients with cancers. Thus, these markers have potential to be used as biomarkers for prognosis and predictive indicator of patients with cancers. For instance, a higher level of ALDH1 was significantly associated with cancer recurrence and poor prognosis in breast, esophageal, colorectal, lung, gastric, acute myeloid lymphoma, and head & neck cancer. Aberrant expression of SOX2 is associated with clinicopathological factors in various types of cancers such as chemotherapy resistance in colorectal cancer (CRC), stages and metastasis of breast carcinomas, advanced tumor stage, poor prognosis in gastric cancers, etc. Similarly, deregulation of Oct-3/4 expression is correlated with neoplastic transformation and therapy resistance in patients with various cancers. In CRC, for instance, an increase of Oct-3/4 is associated with migration, liver metastasis, and poor survival. In addition, higher expression of Oct-3/4 in CSCs is associated with the initiation, progression, and differentiation of breast cancer, micro-metastases in hepatocellular carcinoma (HCC), and poor survival of patients with lung cancers. In addition, overexpression of other CSC markers such as Bmi1 correlated poor overall survival in patients with breast cancer. Overexpression of LETM1 is associated with a poor prognosis in patients with CRC. Furthermore, overexpression of Msi2 correlated with higher tumor grade and poor prognosis in patients with gastric cancer, HCC, and cervical cancers. Moreover, overexpression of Sall4 is associated with lymph node metastasis in patients with CRC. Therefore, the intracellular CSC marker has the potential to be used as an potential indicators in different types of cancer. Thus, in this chapter we summarize the potential diagnostic and prognostic implication of intracellular marker of CSCs, which could provide better option for the management of patients with cancers.KeywordsIntracellular factorALDH1SOX2Oct-3/4Bmi1LETM1Msi2Sall4
