SH3BGRL as a novel prognostic biomarker is down-regulated in acute myeloid leukemia

Xu, Lixia; Zhang, Mingming; Li, Hui; Guan, Wen; Liu, Bin; Liu, Fengqi; Wang, Hehua; Li, Juan; Yang, Shulan; Tong, Xiuzhen; Wang, Haihe

doi:10.1080/10428194.2017.1344843

Cited by 14 publications

(12 citation statements)

References 31 publications

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“…Our previous results unmasked a novel role of mouse SH3BGRL (mSH3BGRL) in driving colorectal cancer metastasis through c-Src activation, but the inverse role of human SH3BGRL as a tumor suppressor [16]. The later study further verified the suppression role of human SH3BGRL in leukemogenesis [17]. Clinically, SH3BGRL is highly upregulated in breast tumors and squamous oral carcinoma, implying its possible tumor-promoting role in these contexts [15,18,19].…”

Section: Introductionmentioning

confidence: 55%

“…However, SH3BGRL is observed to be broadly upregulated in breast tumors, including squamous oral carcinoma, among which only rare patients contain somatic mutation, such as R76C which can mimic the mouse SH3BGRL to enhance tumorigenesis and metastasis. In contrast, low SH3BGRL expression is related to AML progression [17], indicating the dual functions of SH3BGRL in cancer progression. Considering the adaptor character of SH3BGRL, this dual-sided effect might be attributed to the specific cell contexts in different tissues, including HER2 expression state in breast tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Previous results indicate that human SH3BGRL functions as a tumor suppressor [16,17], and only the mutated ones promote tumor metastasis and progression. However, accumulating evidence shows that SH3BGRL is highly upregulated in breast tumors [15,18,19], implying its possibly oncogenic role in breast cancer progression.…”

Section: Sh3bgrl Binds To Her2 Via Its α2 Helix and β3 Sheetmentioning

confidence: 97%

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SH3BGRL confers innate drug resistance in breast cancer by stabilizing HER2 activation on cell membrane

Zhang

Wei

et al. 2020

J Exp Clin Cancer Res

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Background: HER2-positive breast cancer is usually associated to the more aggressive progression and the worse prognosis, but the mechanism underlying the innate resistance to HER2-targeted therapy remains elusive. The scaffold protein SH3-domain-binding glutamic acid-rich protein-like protein (SH3BGRL) is indicated as a tumor suppressor in some cancers, but it is highly expressed in breast cancers. Here we characterized the tumorigenic function of SH3BGRL in HER2-expressing breast cancer cells and the subsequent effect in HER2-targeted therapies. Methods: The interaction of SH3BGRL to HER2 were characterized with various truncated SH3BGRL mutants by immunoprecipitation and molecule docking simulation. The physiological roles of SH3BGRL interacting with HER2 in tumor progression and therapy implication were characterized by gain and loss of function approaches in vitro and in vivo. Immunohistochemistry was used for detections of SH3BGRL and p-HER2 (Y1196) expressions in xenografted tumors and human breast cancer tissues. Clinical relevance of SH3BGRL expression with HER2 was validated with both breast patient sample and the public data analyses. Results: Our results demonstrated that SH3BGRL directly binds with HER2 on cell membrane via its motifs α1, α2 helixes and β3 sheet, which postpones HER2 internalization upon EGF stimulation. Consequently, the association between SH3BGRL and HER2 contributed to the prolonged HER2 phosphorylation at specific tyrosine sites, especially at Y1196, and their downstream signaling activation. The relevance between SH3BGRL expression and p-HER2 (Y1196) phosphorylation was validated in both xenografted tumors and the breast cancer patient tissues. Mechanistically, SH3BGRL promoted breast tumor cell proliferation and survival, while reduced the cell sensitivity to anti-tumor drugs, especially to the HER2-targeted drugs. In contrast, Silencing SH3BGRL or inhibiting its downstream signals efficiently induced apoptosis of breast tumor cells with HER2 and SH3BGRL doubly positive expression. Database analysis also highlighted that SH3BGRL is a poor prognostic marker, especially for HER2positive breast cancers.

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Section: Introductionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Sh3bgrl Binds To Her2 Via Its α2 Helix and β3 Sheetmentioning

confidence: 97%

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SH3BGRL confers innate drug resistance in breast cancer by stabilizing HER2 activation on cell membrane

Zhang

Wei

et al. 2020

J Exp Clin Cancer Res

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“…Interesting, Wang et al suggested SH3BGRL may be an oncogene in mice, but as a tumor suppressor gene in human [8]. Xu et al found SH3BGRL as a novel prognostic biomarker is down-regulated in acute myeloid leukemia [9]. Our previous study and another group also found SH3BGRL3 could be as a biomarker in kidney and bladder cancer [10,11].…”

Section: Introductionmentioning

confidence: 62%

SH3BGRL2 inhibits growth and metastasis in clear cell renal cell carcinoma via activating hippo/TEAD1-Twist1 pathway

Yin

et al. 2020

EBioMedicine

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Background: Clear cell renal cell carcinoma (ccRCC) is one of the most prevalent malignancies in the world, and tumor metastasis is still the main reason for disease progression. Accumulating evidence shows that SH3BGRL2 may play a key role in tumor progression and metastasis. However, the role of SH3BGRL2 in ccRCC has not been systematically investigated and remains elusive. Methods: The clinical significance of SH3BGRL2 was evaluated by bioinformatic analysis and tissue microarray (TMA) samples. SH3BGRL2 expression was determined by RT-PCR, western blot and immunohistochemistry staining. Tumor suppressive effect of SH3BGRL2 was determined by both in vitro and in vivo studies. Western blot, chromatin immunoprecipitation assay and luciferase report assay were applied for mechanism dissection. Findings: SH3BGRL2 was crucial for epithelial-mesenchymal transition (EMT) progression and metastasis in ccRCC. Clinically, SH3BGRL2 was identified as an independent prognostic factor for ccRCC patients. Gain-and loss-of-function results suggested that SH3BGRL2 played a critical role in cell proliferation, migration and invasion. Mechanistically, we found that SH3BGRL2 acted as a tumor suppressor through Hippo/TEAD1 signaling, then TEAD1 altered Twist1 expression at the transcriptional level via directly binding to its promoter region. Interpretation: Our findings established that SH3BGRL2 performed as a tumor suppressor and modulator via Hippo/TEAD1-Twist1 signaling in ccRCC, and the alteration of SH3BGRL2 could serve as a functional response biomarker of tumor progression and metastasis in ccRCC.

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“…The DELs upstream of POU3F4 were also located downstream of SH3BGRL. SH3BGRL was reported to play a role in gastric cancer, acute myeloid leukemia and breast cancer [30][31][32]. However, whether DELs located between POU3F4 and SH3BGRL genes in uence the function of SH3BGRL remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Genetic Findings of Sanger and Nanopore Single-Molecule Sequencing in Patients with X-Linked Hearing Loss and Incomplete Partition Type III

Chen¹,

Qiu²,

Wu³

et al. 2021

Preprint

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BackgroundPOU3F4 is the causative gene for X-linked deafness-2 (DFNX2), characterized by incomplete partition type III (IP-III) malformation of the inner ear. The aim of this study was to investigate the clinical characteristics and molecular findings by Sanger or Nanopore single-molecule sequencing in IP-III patients. MethodsDiagnosis of IP-III was mainly based on clinical characteristics including radiological and audiological findings. Sanger sequencing of POU3F4 were carried out for these IP-III patients. For those patients with negative results for POU3F4 Sanger sequencing, Nanopore long-read single-molecule sequencing was used to identify the possible pathogenic variants. Hearing intervention outcomes of hearing aids fitting and cochlear implantation were also analyzed. Grouped by different locations of POU3F4 variants, aided PTA was further compared between patients in whom the variants located in the exon region or in the upstream region.ResultsIn total, 18 male patients from 14 unrelated families were diagnosed with IP-III. 10 variants were identified in POU3F4 by Sanger sequencing and 9 of these were novel (p.Val321Gly, p.Gln181*, p.Cys233*, p.Val215Gly, p.Arg282Gln, p.Trp57*, p.Gln316*, c.903_912 delins TGCCA and p.Arg205del). Four different deletions (DELs) that varied from 80 to 486 kb were identified 876-1503 kb upstream of POU3F4 by Nanopore long-read single-molecule sequencing. Of them, de novo genetic mutations occurred in 21.4% (3/14) of patients with POU3F4 mutations. Of these 18 patients, 7 had bilateral hearing aids (HAs) and 10 patients received unilateral cochlear implantation (CI). The mean aided pure tone average (PTA) for HAs and CI users were 41.1±5.18 and 40.3±7.59 dB HL respectively. The mean PTAs for whom the variants located in the exon and upstream regions were 39.6±6.31 vs 43.0±7.10 dB HL, which presented no significant difference (p=0.342).ConclusionsAmong IP-III patients, 28.6% (4/14) had no definite mutation in exon region of POU3F4, however, possible pathogenic deletions were identified in upstream region of this gen. De novo genetic mutations occurred in 21.4% (3/14) of patients with POU3F4 mutation. Hearing intervention outcomes of IP-III patients presented no difference regardless of the variants locations on exon or upstream regions.

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SH3BGRL as a novel prognostic biomarker is down-regulated in acute myeloid leukemia

Cited by 14 publications

References 31 publications

SH3BGRL confers innate drug resistance in breast cancer by stabilizing HER2 activation on cell membrane

SH3BGRL confers innate drug resistance in breast cancer by stabilizing HER2 activation on cell membrane

SH3BGRL2 inhibits growth and metastasis in clear cell renal cell carcinoma via activating hippo/TEAD1-Twist1 pathway

Genetic Findings of Sanger and Nanopore Single-Molecule Sequencing in Patients with X-Linked Hearing Loss and Incomplete Partition Type III

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