Uncovering the potential of <scp>CD</scp>44v/<scp>SYNE</scp>1/miR34a axis in salivary fluids of oral cancer patients

Shah, Kavan; Patel, Shanaya; Modi, Bansri; Shah, Franky D.; Rawal, Rakesh

doi:10.1111/jop.12678

Cited by 28 publications

(17 citation statements)

References 29 publications

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“…It has been evident that CD44 as a surface biomarker of cancer stem cells (CSCs) and a vital regulatory factor of epithelial-mesenchymal transition (EMT) program is involved in the regulation of tumor initiation and development [6,[15][16][17]. Aberrant expression of CD44 and dysregulation of CD44 contribute to tumor formation of multiple cancer entities, including lung cancer [18], hepatocellular carcinoma [19], ovarian cancer [20], glioma [21], papillary thyroid carcinoma [22], head and neck squamous cell carcinoma (HNSCC) [23], astrocytic gliomas [24] and oral squamous cell carcinoma (OSCC) [25]. In hepatocellular carcinoma cells (HuH7) which originally express CD44s rather than CD44v, silence of CD44 gene impaired the potential of spheroid formation and enhanced sensitivity to sorafenib and 5-fluorouracil (5-FU), accompanied by remarkable downregulation of CSC-related genes including CD133 and EpCAM [19].…”

Section: Open Accessmentioning

confidence: 99%

CD44 as a tumor biomarker and therapeutic target

et al. 2020

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CD44, a complex transmembrane glycoprotein, exists in multiple molecular forms, including the standard isoform CD44s and CD44 variant isoforms. CD44 participates in multiple physiological processes, and aberrant expression and dysregulation of CD44 contribute to tumor initiation and progression. CD44 represents a common biomarker of cancer stem cells, and promotes epithelial-mesenchymal transition. CD44 is involved in the regulation of diverse vital signaling pathways that modulate cancer proliferation, invasion, metastasis and therapy-resistance, and it is also modulated by a variety of molecules in cancer cells. In addition, CD44 can serve as an adverse prognostic marker among cancer population. The pleiotropic roles of CD44 in carcinoma potentially offering new molecular target for therapeutic intervention. Preclinical and clinical trials for evaluating the pharmacokinetics, efficacy and drug-related toxicity of CD44 monoclonal antibody have been carried out among tumors with CD44 expression. In this review, we focus on current data relevant to CD44, and outline CD44 structure, the regulation of CD44, functional properties of CD44 in carcinogenesis and cancer progression as well as the potential CD44-targeting therapy for cancer management.

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Section: Open Accessmentioning

confidence: 99%

CD44 as a tumor biomarker and therapeutic target

et al. 2020

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“…Searching for a suggested contribution of CD44v6 to miRNA processing revealed reduced recovery of 28 miRNA in CD44v6kd cells, only 7 miRNA being also reduced in Tspan8kd but none only in Tspan8kd cells. The impact of CD44v6 on miRNA recovery [32] is in line with the CD44v6-Dicer and -Argonaute (Ago) associations [73, 74]. Furthermore, reduced miRNA expression in CD44v6kd, but not Tspan8kd cells, argues against Tspan8 engagement in miRNA processing.…”

Section: Discussionmentioning

confidence: 79%

The Pancreatic Cancer-Initiating Cell Marker CD44v6 Affects Transcription, Translation, and Signaling: Consequences for Exosome Composition and Delivery

Sun

Rana

Wang

et al. 2019

Journal of Oncology

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Pancreatic cancer-initiating cells (PaCIC) express CD44v6 and Tspan8. A knockdown (kd) of these markers hinders the metastatic capacity, which can be rescued, if the cells are exposed to CIC-exosomes (TEX). Additional evidence that CD44v6 regulates Tspan8 expression prompted us to explore the impact of these PaCIC markers on nonmetastatic PaCa and PaCIC-TEX. We performed proteome, miRNA, and mRNA deep sequencing analyses on wild-type, CD44v6kd, and Tspan8kd human PaCIC and TEX. Database comparative analyses were controlled by qRT-PCR, Western blot, flow cytometry, and confocal microscopy. Transcriptome analysis of CD44 versus CD44v6 coimmunoprecipitating proteins in cells and TEX revealed that Tspan8, several signal-transducing molecules including RTK, EMT-related transcription factors, and proteins engaged in mRNA processing selectively associate with CD44v6 and that the membrane-attached CD44 intracytoplasmic tail supports Tspan8 and NOTCH transcription. Deep sequencing uncovered a CD44v6 contribution to miRNA processing. Due to the association of CD44v6 with Tspan8 in internalization prone tetraspanin-enriched membrane domains (TEM) and the engagement of Tspan8 in exosome biogenesis, most CD44v6-dependent changes were transferred into TEX such that the input of CD44v6 to TEX activities becomes largely waved in both a CD44v6kd and a Tspan8kd. Few differences between CD44v6kd- and Tspan8kd-TEX rely on CD44v6 being also recovered in non-TEM derived TEX, highlighting distinct TEX delivery from individual cells that jointly account for TEX-promoted target modulation. This leads us to propose a model in which CD44v6 strongly supports tumor progression by cooperating with signaling molecules, altering transcription of key molecules, and through its association with the mRNA processing machinery. The association of CD44v6 with Tspan8, which plays a crucial role in vesicle biogenesis, promotes metastases by transferring CD44v6 activities into TEM and TEM-independently derived TEX. Further investigations of the lead position of CD44v6 in shifting metastasis-promoting activities into CIC-TEX may offer a means of targeting TEX-CD44v6 in therapeutic applications.

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“…These findings are critically important as more evidence accumulates that suggest subpopulations of CSC may be critical factors in determining the treatment strategy and overall prognosis in oral cancer patients (Ravindran et al, 2015;Mohanta et al, 2017;He et al, 2014). In fact, new evidence suggests that metastatic potential and invasiveness may be heavily dependent upon these CSC subpopulations, therefore more information regarding their properties and survival in well-characterized systems will be critical to further our understanding of these phenomenon (Rodrigues et al, 2018;Shah et al, 2018;Chen et al, 2018). As more studies evaluate the role of CSC in oral cancer, more accurate and predictive models of therapy and prognosis will be needed to more effectively treat and manage patient care (Teixeira and Corrêa, 2018;Castilho et al, 2017).…”

Section: Resultsmentioning

confidence: 99%

Isolation and Identification of Oral Cancer Stem Cells (CSC) within Commercially Available Cell Lines

Chauncey¹,

Hatch²,

Jilka³

et al. 2018

Current Research in Dentistry

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Previous studies have demonstrated some tumors develop or maintain a small sub-population of cells with stem cell-like properties. This Cancer Stem Cells (CSC) may exhibit differential properties that allow their escape from traditional radiation or chemotherapy treatments and may therefore be responsible for cancer recurrence. Few studies have explored this phenomenon among oral cancer cell lines, therefore the objective of this study was to examine multiple oral cancer cell lines to determine if any or all contained subpopulations of CSCs. Multiple commercially available Oral Squamous Carcinoma Cell (OSCC) lines were obtained for this study, including SCC15, SCC25 and CAL27. Cells were cultured for CSC screening and isolation. RNA was isolated from any potential CSC isolates for biomarker screening and verification. All OSCC lines examined developed adhesion-independent tumor spheres (AiTS), a characteristic phenotype of oral CSC. Each AiTS was manually isolated for separate, independent culture and analysis. RNA extracted from the AiTS revealed differential expression of specific CSC markers, including CD44, CD133, ABCG, CXCR6 and NANOG. These biomarkers were not observed in RNA extracted from the remaining non-CSC cell cultures. Although a previous study from this group successfully isolated AiTS from one cervical and one oral cancer cell line, this may be the first study to isolate CSC from multiple oral cancer cell lines and verify both cell-surface and intracellular CSC biomarkers. These results may suggest that many tumors and oral cancers could harbor AiTS and CSC and that screening for these sub-populations may provide guidance for treatment and therapy to improve oral cancer survival rates.

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Uncovering the potential of CD44v/SYNE1/miR34a axis in salivary fluids of oral cancer patients

Abstract: Collectively, these findings suggested a plausible role of CD44v/SYNE1/miR34a axis as non-invasive salivary biomarkers to diagnose this disease at an early stage and predict the early onset of metastasis.

Cited by 28 publications

References 29 publications

CD44 as a tumor biomarker and therapeutic target

CD44 as a tumor biomarker and therapeutic target

The Pancreatic Cancer-Initiating Cell Marker CD44v6 Affects Transcription, Translation, and Signaling: Consequences for Exosome Composition and Delivery

Isolation and Identification of Oral Cancer Stem Cells (CSC) within Commercially Available Cell Lines

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