Decreased<i>SMAD4</i>expression is associated with induction of epithelial-to-mesenchymal transition and cetuximab resistance in head and neck squamous cell carcinoma

Cheng, Haixia; Fertig, Elana J.; Ozawa, Hiroyuki; Hatakeyama, Hyōe; Howard, Jason D.; Pérez, Jimena; Considine, Michael; Thakar, Manjusha; Ranaweera, Ruchira S.; Krigsfeld, Gabriel; Chung, Christine H.

doi:10.1080/15384047.2015.1056418

Cited by 35 publications

(51 citation statements)

References 38 publications

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“…SMAD4 expression was detected in 86.9% of patients, but was undetectable in 6 (4.6%) tumors (Supplemental Table 1). This is consistent with 7% of HNSCC having SMAD4 alteration via homozygous deletion, and nonsense, missense, and silent mutations resulting in complete loss, while relative downregulation of SMAD4 expression is more commonly seen in 44.8% of HNSCC based on the gene expression analysis of TCGA dataset as previously published by our group (27). Of the 6 SMAD4 negative patients, 5 patients had a tumor site other than the oropharynx and were HPV negative.…”

Section: Resultssupporting

confidence: 90%

“…We have previously shown that in HNSCC obtained from TCGA dataset, HPV-negative tumors are more likely to have lower SMAD4 expression than HPV-positive HNSCC (27). Furthermore, we showed that decreased SMAD4 expression induces HPV-negative tumor cells to undergo EMT and renders them resistant to the EGFR inhibitor cetuximab (27).…”

Section: Discussionmentioning

confidence: 99%

“…For example, loss of SMAD4 promotes pancreatic and colorectal tumor progression and is strongly associated with increased metastatic potential, lower overall survival and poor chemotherapeutic responses (23–25). Likewise, loss of SMAD4 activity was reported to cause spontaneous HNSCC formation, to induce epithelial-to-mesenchymal transition (EMT) and cetuximab resistance, and to result in genomic instability through the downregulation of DNA repair-related genes (18, 26, 27). Although the link between SMAD4 loss or inactivation and tumorigenesis is strong and compelling, mechanisms underlying the resistance to cetuximab, an FDA approved HNSCC targeted therapy, in tumors with SMAD4 loss has not been reported.…”

Section: Introductionmentioning

confidence: 99%

“…Previously, we demonstrated that cetuximab resistant clones of an HPV-negative HNSCC cell line had reduced SMAD4 gene expression (27). Interestingly, HPV-negative tumors in HNSCC patients also had lower SMAD4 expression compared to HPV-positive tumors, suggesting that the worse overall survival of HPV-negative HNSCC patients may be in part due to low SMAD4 expression.…”

Section: Introductionmentioning

confidence: 99%

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SMAD4 Loss Is Associated with Cetuximab Resistance and Induction of MAPK/JNK Activation in Head and Neck Cancer Cells

Ozawa

Ranaweera

Izumchenko

et al. 2017

Clinical Cancer Research

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Purpose We previously demonstrated an association between decreased SMAD4 expression and cetuximab resistance in head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to further elucidate the clinical relevance of SMAD4 loss in HNSCC. Experimental Design SMAD4 expression was assessed by immunohistochemistry in 130 newly diagnosed and 43 recurrent HNSCC patients. Correlative statistical analysis with clinicopathological data was also performed. OncoFinder, a bioinformatics tool, was used to analyze molecular signaling in TCGA tumors with low or high SMAD4 mRNA levels. The role of SMAD4 was investigated by shRNA knockdown and gene reconstitution of HPV-negative HNSCC cell lines in vitro and in vivo. Results Our analysis revealed that SMAD4 loss was associated with an aggressive, HPV-negative, cetuximab-resistant phenotype. We found a signature of pro-survival and anti-apoptotic pathways that were commonly dysregulated in SMAD4-low cases derived from TCGA-HNSCC dataset and an independent oral cavity squamous cell carcinoma (OSCC) cohort obtained from GEO. We show that SMAD4 depletion in a HNSCC cell line induces cetuximab resistance and results in worse survival in an orthotopic mouse model in vivo. We implicate JNK and MAPK activation as mediators of cetuximab resistance and provide the foundation for the concomitant EGFR and JNK/MAPK inhibition as a potential strategy for overcoming cetuximab resistance in HNSCCs with SMAD4 loss. Conclusions Our study demonstrates that loss of SMAD4 expression is a signature characterizing the cetuximab-resistant phenotype and suggests that SMAD4 expression may be a determinant of sensitivity/resistance to EGFR/MAPK or EGFR/JNK inhibition in HPV-negative HNSCC tumors.

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Section: Resultssupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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SMAD4 Loss Is Associated with Cetuximab Resistance and Induction of MAPK/JNK Activation in Head and Neck Cancer Cells

Ozawa

Ranaweera

Izumchenko

et al. 2017

Clinical Cancer Research

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“…Perturbation of the TGFβ pathway-including the two TGFβ superfamily receptors TGFBR2 and ACVR2A and their downstream effector, the transcription factor SMAD4-all showed phenotypes. SMAD4 loss has been shown previously to impact resistance to EGFRis (Cheng et al 2015), but how it suppresses EGFRi sensitivity is not known. Other key pathways illustrated in the screen involved proliferation and survival.…”

Section: Discussionmentioning

confidence: 99%

A genetic interaction analysis identifies cancer drivers that modify EGFR dependency

et al. 2017

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A large number of cancer drivers have been identified through tumor sequencing efforts, but how they interact and the degree to which they can substitute for each other have not been systematically explored. To comprehensively investigate how cancer drivers genetically interact, we searched for modifiers of epidermal growth factor receptor (EGFR) dependency by performing CRISPR, shRNA, and expression screens in a non-small cell lung cancer (NSCLC) model. We elucidated a broad spectrum of tumor suppressor genes (TSGs) and oncogenes (OGs) that can genetically modify proliferation and survival of cancer cells when EGFR signaling is altered. These include genes already known to mediate EGFR inhibitor resistance as well as many TSGs not previously connected to EGFR and whose biological functions in tumorigenesis are not well understood. We show that mutation of PBRM1, a subunit of the SWI/SNF complex, attenuates the effects of EGFR inhibition in part by sustaining AKT signaling. We also show that mutation of Capicua (CIC), a transcriptional repressor, suppresses the effects of EGFR inhibition by partially restoring the EGFR-promoted gene expression program, including the sustained expression of Ets transcription factors such as ETV1. Together, our data provide strong support for the hypothesis that many cancer drivers can substitute for each other in certain contexts and broaden our understanding of EGFR regulation.

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Down‐regulation of miR‐146a‐5p and its potential targets in hepatocellular carcinoma validated by a TCGA‐ and GEO‐based study

Zhang

Liang

et al. 2017

FEBS Open Bio

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Our previous research has demonstrated that miR‐146a‐5p is down‐regulated in hepatocellular carcinoma (HCC) and might play a tumor‐suppressive role. In this study, we sought to validate the decreased expression with a larger cohort and to explore potential molecular mechanisms. GEO and TCGA databases were used to gather miR‐146a‐5p expression data in HCC, which included 762 HCC and 454 noncancerous liver tissues. A meta‐analysis of the GEO‐based microarrays, TCGA‐based RNA‐seq data, and additional qRT‐PCR data validated the down‐regulation of miR‐146a‐5p in HCC and no publication bias was observed. Integrated genes were generated by overlapping miR‐146a‐5p‐related genes from predicted and formerly reported HCC‐related genes using natural language processing. The overlaps were comprehensively analyzed to discover the potential gene signatures, regulatory pathways, and networks of miR‐146a‐5p in HCC. A total of 251 miR‐146a‐5p potential target genes were predicted by bioinformatics platforms and 104 genes were considered as both HCC‐ and miR‐146a‐5p‐related overlaps. RAC1 was the most connected hub gene for miR‐146a‐5p and four pathways with high enrichment (VEGF signaling pathway, adherens junction, toll‐like receptor signaling pathway, and neurotrophin signaling pathway) were denoted for the overlapped genes. The down‐regulation of miR‐146a‐5p in HCC has been validated with the most complete data possible. The potential gene signatures, regulatory pathways, and networks identified for miR‐146a‐5p in HCC could prove useful for molecular‐targeted diagnostics and therapeutics.

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DecreasedSMAD4expression is associated with induction of epithelial-to-mesenchymal transition and cetuximab resistance in head and neck squamous cell carcinoma

Cited by 35 publications

References 38 publications

SMAD4 Loss Is Associated with Cetuximab Resistance and Induction of MAPK/JNK Activation in Head and Neck Cancer Cells

SMAD4 Loss Is Associated with Cetuximab Resistance and Induction of MAPK/JNK Activation in Head and Neck Cancer Cells

A genetic interaction analysis identifies cancer drivers that modify EGFR dependency

Down‐regulation of miR‐146a‐5p and its potential targets in hepatocellular carcinoma validated by a TCGA‐ and GEO‐based study

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