The HNRNPA2B1–MST1R–Akt axis contributes to epithelial-to-mesenchymal transition in head and neck cancer

Gupta, Amit; Yadav, Sandhya; Pt, Archana; Mishra, Jharna; Samaiya, Atul; Panday, Rajendra Kumar; Shukla, Sanjeev

doi:10.1038/s41374-020-0466-8

Cited by 22 publications

(22 citation statements)

References 76 publications

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“…In head and neck cancer, HNRNPA2B1 has also been reported to contribute to EMT by regulating the splicing events of oncogenes (Gupta et al, 2020). Moreover, the loss of HNRNPA2B1 in ovarian cancer cells could inhibit malignant capability and promote apoptosis (Yang et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, lncRNA H19 binding to HNRNPA2B1 was able to promote colorectal cancer metastasis by inducing epithelial-to-mesenchymal transition (EMT) ( Zhang et al, 2020 ). In head and neck cancer, HNRNPA2B1 has also been reported to contribute to EMT by regulating the splicing events of oncogenes ( Gupta et al, 2020 ). Moreover, the loss of HNRNPA2B1 in ovarian cancer cells could inhibit malignant capability and promote apoptosis ( Yang et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

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HNRNPA2B1 Affects the Prognosis of Esophageal Cancer by Regulating the miR-17-92 Cluster

Chen

Lou

et al. 2021

Front. Cell Dev. Biol.

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N6-methyladenosine (m6A) is the most abundant RNA modification in eukaryotes. Accumulating evidence suggests that dysregulation of m6A modification significantly correlates with tumorigenesis and progression. In this study, we observed an increased expression and positive correlations of all 25 m6A regulators in esophageal cancer (ESCA) data obtained from the TCGA database. Through expression profiling of these regulators, a prognostic score model containing HNRNPA2B1, ALKBH5, and HNRNPG was established, and the high-risk subgroup exhibited strong positive correlations with ESCA progression and outcome. The risk score obtained from this model may represent an independent predictor of ESCA prognosis. Notably, the gene most frequently associated with increased risk was HNRNPA2B1; in ESCA, the increased expression of this gene alone predicted poor prognosis by affecting tumor-promoting signaling pathways through miR-17-92 cluster. An experimental study demonstrated that elevated HNRNPA2B1 expression was positively associated with distant metastasis and lymph node stage, and predicted the poor outcomes of ESCA patients. Knockdown of HNRNPA2B1 significantly decreased the expression of miR-17, miR-18a, miR-20a, miR-93, and miR-106b and inhibited the proliferation of ESCA cells. Therefore, our study indicated that the dynamic changes in 25 m6A regulators were associated with the clinical features and prognosis of patients with ESCA. Importantly, HNRNPA2B1 alone may affect the prognosis of patients with ESCA by regulating the miR-17-92 cluster.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

HNRNPA2B1 Affects the Prognosis of Esophageal Cancer by Regulating the miR-17-92 Cluster

Chen

Lou

et al. 2021

Front. Cell Dev. Biol.

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“…The process of AS is found to be deregulated in cancer which, in turn, favors the tumor progression ( Ladomery, 2013 ). Expression of cancer-specific isoforms of various genes in cancer cells is majorly due to epigenetic modifications at the gene locus ( Singh et al, 2017 ) as well as due to the deregulation of splicing factors which include the SR protein family and HnRNP family members ( Gupta et al, 2020 ). In fact, a large number of splicing factors have been reported to be deregulated in multiple cancer types, and have been found to be responsible for aberrant AS.…”

Section: Discussionmentioning

confidence: 99%

“…These splicing regulators bind to the specific sequence of the target genes and affect inclusion or exclusion of the exon, thereby regulates the expression of different transcripts from a single gene which further controls the key cellular process. A large number of splicing factors have been reported to be deregulated in multiple cancer types ( Boukakis et al, 2010 ; Silipo et al, 2015 ) and thus found to be responsible for aberrant AS ( Gupta et al, 2020 ). The deregulation of these splicing factors is governed by the triggering of several cellular signaling pathways, eventually leading to altered regulation of AS events ( Blaustein et al, 2007 ).…”

Section: Introductionmentioning

confidence: 99%

ERK1/2-EGR1-SRSF10 Axis Mediated Alternative Splicing Plays a Critical Role in Head and Neck Cancer

Yadav

Pant

Samaiya

et al. 2021

Front. Cell Dev. Biol.

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Aberrant alternative splicing is recognized to promote cancer pathogenesis, but the underlying mechanism is yet to be clear. Here, in this study, we report the frequent upregulation of SRSF10 (serine and arginine-rich splicing factor 10), a member of an expanded family of SR splicing factors, in the head and neck cancer (HNC) patients sample in comparison to paired normal tissues. We observed that SRSF10 plays a crucial role in HNC tumorigenesis by affecting the pro-death, pro-survical splice variants of BCL2L1 (BCL2 Like 1: BCLx: Apoptosis Regulator) and the two splice variants of PKM (Pyruvate kinase M), PKM1 normal isoform to PKM2 cancer-specific isoform. SRSF10 is a unique splicing factor with a similar domain organization to that of SR proteins but functions differently as it acts as a sequence-specific splicing activator in its phosphorylated form. Although a body of research studied the role of SRSF10 in the splicing process, the regulatory mechanisms underlying SRSF10 upregulation in the tumor are not very clear. In this study, we aim to dissect the pathway that regulates the SRSF10 upregulation in HNC. Our results uncover the role of transcription factor EGR1 (Early Growth Response1) in elevating the SRSF10 expression; EGR1 binds to the promoter of SRSF10 and promotes TET1 binding leading to the CpG demethylation (hydroxymethylation) in the adjacent position of the EGR1 binding motif, which thereby instigate SRSF10 expression in HNC. Interestingly we also observed that the EGR1 level is in the sink with the ERK1/2 pathway, and therefore, inhibition of the ERK1/2 pathway leads to the decreased EGR1 and SRSF10 expression level. Together, this is the first report to the best of our knowledge where we characterize the ERK 1/2-EGR1-SRSF10 axis regulating the cancer-specific splicing, which plays a critical role in HNC and could be a therapeutic target for better management of HNC patients.

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“…Codon optimization was employed in constructing the hnRNPA2B1 plasmid. The hnRNPA2 overexpression plasmid was constructed by amplifying the hnRNPA2 fragment through gene synthesis ( Gupta et al, 2020 ). Lentiviral plasmids were transfected into HEK-293T cells along with the packaging plasmid psPAX2 (Addgene#12,260) and envelope plasmid pMD2.G (Addgene#12,259) using the Lipofectamine 3,000 reagent (Invitrogen, Carlsbad, CA, United States).…”

Section: Methodsmentioning

confidence: 99%

hnRNPA2B1 Promotes Colon Cancer Progression via the MAPK Pathway

et al. 2021

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HNRNPA2B1, an RNA-binding protein, plays a key role in primary microRNA processing, alternative splicing, mRNA metabolism and transport. Interestingly, hnRNPA2B1 also works as an N6-methyladenosine (m6A) reader and is critical during tumorigenesis of various tissue types. However, its role in colon cancer is still unclear. In this study, we aimed to elucidate the biological functions of hnRNPA2B1 and to explore its underlying mechanisms in colon cancer. We examined the expression of hnRNPA2B1 in Oncomine and TCGA databases. Then verified the findings in colon cancer cells and clinical samples with western blotting and immunohistochemistry (IHC). We used CRISPR/Cas9 directed gene editing to knockout hnRNPA2B1 expression in human colon cancer cell line SW480 and HCT-116 and carried out both in vivo and in vitro experiments. The results were further confirmed by RNA-seq analyses. We found that hnRNPA2B1 significantly promoted colon cancer cell proliferation both in vitro and in vivo, while knockout of hnRNPA2B1 induced apoptosis and cell cycle arrest in SW480. RNA-seq analyses revealed that the ERK/MAPK pathway was activated by hnRNPA2B1 upregulation. In addition, both hnRNPA2B1 and MAPK pathway were activated in clinical colon cancer specimens and positively correlated. Mechanistically, hnRNPA2B1 appeared to be an upstream regulator of the ERK/MAPK pathway and inhibition of MAPK signaling blocked the effects of hnRNPA2B1. Taken together, our data demonstrated that the RNA-binding protein hnRNPA2B1 promotes cell proliferation and regulates cell cycle and apoptosis of human colon cancer by activating the ERK/MAPK signaling, which may provide a new insight into the development of hnRNPA2B1 as a potential therapeutic target for treatment of colon cancer.

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The HNRNPA2B1–MST1R–Akt axis contributes to epithelial-to-mesenchymal transition in head and neck cancer

Cited by 22 publications

References 76 publications

HNRNPA2B1 Affects the Prognosis of Esophageal Cancer by Regulating the miR-17-92 Cluster

HNRNPA2B1 Affects the Prognosis of Esophageal Cancer by Regulating the miR-17-92 Cluster

ERK1/2-EGR1-SRSF10 Axis Mediated Alternative Splicing Plays a Critical Role in Head and Neck Cancer

hnRNPA2B1 Promotes Colon Cancer Progression via the MAPK Pathway

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