Genomic characterization of tobacco/nut chewing HPV-negative early stage tongue tumors identify MMP10 as a candidate to predict metastases

Upadhyay, Pawan; Gardi, Nilesh; Desai, Sanket; Chandrani, Pratik; Joshi, Asim; Dharavath, Bhaskar; Arora, Priyanca; Bal, Munita; Nair, Sudhir; Dutt, Amit

doi:10.1016/j.oraloncology.2017.08.003

Cited by 39 publications

(38 citation statements)

References 53 publications

(74 reference statements)

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“…Reported mutation burden in oral squamous cell carcinoma is between 2 and 12 mutations per MB. 10,11 We observed 10 mutations per MB in cells treated with shisha extract with similar mutation spectrum as reported in whole-exome sequence analysis study of 15 OSCC patients with history of Shamma exposure. 25 In addition, missense variant(s) were identified in SAM and SH3 domain containing 1 (SASH1), Filamin C (FLNC), and Adenylate Cyclase 8 (ADCY8) with >30% allele frequency supported by at least 10 reads and predicted to be deleterious by ≥3…”

Section: Discussionsupporting

confidence: 81%

“…8 A comparative study on exposure to tobacco-specific nitrosamines (NNAL) in shisha smokers, cigarette smokers, and non-smokers has shown that regular shisha smokers are exposed to about 5-10 times greater quantities of nitrosamines than non-smokers which is equivalent to pack-a-day cigarette smokers. 9 Risk associations and pathogenesis of oral cancer is well documented 10,11 ; however, it is not extensively studied in shisha smokers. We developed a cell line model using immortalized normal oral keratinocytes by chronically treating them with shisha extract for a period of 8 months.…”

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confidence: 99%

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Multiomic analysis of oral keratinocytes chronically exposed to shisha

Patil

Patel

Advani

et al. 2019

J Oral Pathology Medicine

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Background Tobacco is smoked in different form including cigarettes and water pipes. One popular form of water pipe smoking especially in Middle Eastern countries is shisha smoking. Shisha has been associated with various diseases including oral cancer. However, genomic alterations and gene expression changes associated with chronic shisha exposure have not been previously investigated. Objectives Whole‐exome sequencing and gene expression profiling of immortalized human oral keratinocytes (OKF6/TERT1) cells chronically treated with 0.5% shisha extract for a period of 8 months was undertaken to characterize molecular alterations associated with shisha exposure. Methods Genomic DNA and RNA were extracted and preprocessed as per manufacturer's instruction and subjected to whole‐exome and transcriptome sequencing using Illumina HiSeq2500 platform. Exome was analyzed using GATK pipeline whereas RNA‐Seq data was analyzed using HiSat2 and HTSeq along with DESeq to elucidate differentially expressed genes. Results Whole‐exome sequence analysis led to identification of 521 somatic missense variants corresponding to 389 genes RNA‐Seq data revealed 247 differentially expressed genes (≥2‐fold, P‐value<0.01) in shisha treated cells compared to parental cells. Pathway analysis of differentially expressed genes revealed that interferon‐signaling pathway was significantly affected. We predict activation of MAPK1 pathway which is known to play a key role in oral cancer. We also observed allele specific expression of mutant LIMA1 based on RNA‐Seq dataset. Conclusion Our findings provide insights into genomic alterations and gene expression pattern associated with oral keratinocytes chronically exposed to shisha.

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Section: Discussionsupporting

confidence: 81%

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confidence: 99%

Multiomic analysis of oral keratinocytes chronically exposed to shisha

Patil

Patel

Advani

et al. 2019

J Oral Pathology Medicine

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“…Interestingly, MMP10 and MMP13 are both members of matrix metalloproteinase family and promote cell invasion and metastases. A previous study indicated that MMP10 might be a potential prognostic biomarker for oral cancer metastases . GDF15, another validated candidate gene downstream of LINC01133, belongs to the TGF‐β superfamily.…”

Section: Resultsmentioning

confidence: 99%

“…A previous study indicated that MMP10 might be a potential prognostic biomarker for oral cancer metastases. 24 GDF15, another validated candidate gene downstream of LINC01133, belongs to the TGF-β superfamily. Multiple studies have demonstrated that GDF15 and other TGF-β superfamily members promote metastases of malignant tumors, including OSCC.…”

Section: Transcriptome Expression Analysis Viamentioning

confidence: 99%

Long noncoding RNA LINC01133 inhibits oral squamous cell carcinoma metastasis through a feedback regulation loop with GDF15

Kong

Sun

Zhu

et al. 2018

Journal of Surgical Oncology

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Background and Objectives Long noncoding RNAs (lncRNAs) play key roles in carcinoma metastasis. We aimed to investigate lncRNA LINC01133 in oral squamous cell carcinoma (OSCC) metastasis. Methods The RNA levels of LINC01133 and growth and differentiation factor 15 (GDF15) in tissue samples from OSCC patients, and OSCC cell lines were tested by real‐time quantitative polymerase chain reaction (RT‐qPCR). SPSS20.0 was used to perform statistical analysis of LINC01133 expression in clinical samples and correlate expression of LINC01133 and GDF15. Cell migration/invasion was assessed via transwell assays. Downstream genes of LINC01133 were screened using RNA‐seq and validated by RT‐qPCR. GDF15 protein levels were evaluated via Western blot analysis. Results LINC01133 was downregulated in OSCCs; higher expression of LINC01133 in OSCCs was correlated with less metastasis and better prognosis. LINC01133 inhibited OSCC cell migration and invasion. RNA‐seq data showed that LINC01133 inhibited GDF15, and GDF15 could rescue inhibition of OSCC cell migration and invasion caused by LINC01133. Interestingly, GDF15 also inhibited LINC01133. Furthermore, a significant negative correlation between expression of LINC01133 and GDF15 was validated in the clinical study. Conclusions Collectively, these data indicate that LINC01133 inhibited OSCC metastasis via a feedback regulation loop of reciprocal inhibition with GDF15, suggesting a new diagnostic and therapeutic target for OSCC.

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“…It is widely accepted that HNSCC occurs as a result of cumulative genetic/epigenetic abnormalities in cancer-associated genes. However, to date, a limited number of genes have been reported as candidate somatic drivers for HNSCC, including tumor protein p53 (19), Akt1, APC, CCND1, fibroblast growth factor receptor 3 (FGFR3), NOTCH1, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PI3KCA), and phosphatase and tensin homolog (PTEN) (20)(21)(22)(23)(24). In addition, the HNSCC-specific cancer-associated genes/pathways are not well illustrated.…”

Section: Discussionmentioning

confidence: 99%

DKK3 knockdown confers negative effects on the malignant potency of head and neck squamous cell carcinoma cells via the PI3K/Akt and MAPK signaling pathways

et al. 2018

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Dickkopf-related protein 3 (DKK3), which is a member of the Dickkopf WNT signaling pathway inhibitor family, is considered to be a tumor suppressor, due to its reduced expression in cancer cells and its ability to induce apoptosis when overexpressed by adenovirus. However, our previous study demonstrated alternative functions for DKK3 in head and neck squamous cell carcinoma (HNSCC). Our study reported that DKK3 expression was predominantly upregulated in HNSCC cell lines and tissue samples, and its expression was significantly correlated with poor prognosis. Furthermore, DKK3 overexpression in HNSCC cells significantly increased cancer cell proliferation, migration, invasion and in vivo tumor growth. These data have led to the hypothesis that DKK3 may exert oncogenic functions and may increase the malignant properties of HNSCC. The present study established a stable DKK3 knockdown cell line (HSC-3 shDKK3) using lentivirus-mediated short hairpin RNA, and assessed its effects on cancer cell behavior using MTT, migration and invasion assays. In addition, its effects on in vivo tumor growth were assessed using a xenograft model. Furthermore, the molecular mechanisms underlying the effects of DKK3 knockdown were investigated by microarray analysis, pathway analysis and western blotting. Compared with control cells, HSC-3 shDKK3 cells exhibited significantly reduced proliferation, migration and invasion, and formed significantly smaller tumor masses when subcutaneously transplanted into nude mice. In addition, in HSC-3 shDKK3 cells, the expression levels of phosphorylated (p)-protein kinase B (Akt) (Ser473), p-phosphoinositide 3-kinase (PI3K) p85 (Tyr467), p-PI3K p55 (Try199), p-3-phosphoinositide-dependent protein kinase-1 (PDK1) (Ser241) and total p38 mitogen-activated protein kinase (MAPK) were reduced. Furthermore, phosphorylation of mechanistic target of rapamycin (mTOR) (Ser2448) was slightly decreased in HSC-3 shDKK3 cells, which may be due to the increased expression of DEP domain-containing mTOR-interacting protein. Conversely, DKK3 overexpression in HSC-3 shDKK3 cells rescued cellular proliferation, migration and invasion. With regards to expression levels, p-PI3K and p-PDK1 expression was not altered, whereas mTOR and p-p38 MAPK expression was elevated. These data supported the hypothesis and indicated that DKK3 may contribute to the malignant phenotype of HNSCC cells via the PI3K/Akt/mTOR and MAPK signaling pathways.

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Genomic characterization of tobacco/nut chewing HPV-negative early stage tongue tumors identify MMP10 as a candidate to predict metastases

Abstract: HighlightsPortrait of somatic alterations in HPV-negative early stage tongue tumors with tobacco signature.Upregulation of genes related to EMT pathway identified by transcriptome analysis.MMP10 could be a candidate prognostic biomarker to stratify patients who develop metastases.

Cited by 39 publications

References 53 publications

Multiomic analysis of oral keratinocytes chronically exposed to shisha

Multiomic analysis of oral keratinocytes chronically exposed to shisha

Long noncoding RNA LINC01133 inhibits oral squamous cell carcinoma metastasis through a feedback regulation loop with GDF15

DKK3 knockdown confers negative effects on the malignant potency of head and neck squamous cell carcinoma cells via the PI3K/Akt and MAPK signaling pathways

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