Overexpression of RECQL4 is associated with poor prognosis in patients with gastric cancer

Chen, Honglei; Yuan, Kaitao; Wang, Xinyou; Wang, Huashe; Wu, Qiu-Ning; Wu, Xiaobin; Peng, Junsheng

doi:10.3892/ol.2018.9318

Cited by 12 publications

(16 citation statements)

References 24 publications

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“…However, this could not be addressed in this study given the developmental lethality seen in our homozygous truncating mice. Another (48)(49)(50)(51)(52)(53). We also found that the L638P mutation, which resulted in a stable full-length product with cytoplasmic localization, could not fully rescue the Recql4 deletion.…”

Section: Discussionmentioning

confidence: 90%

“…When using this system to analyze other human mutations, we found that cells overexpressing the human wild type protein could not completely rescue Recql4 deletion, suggesting that overexpression of RECQL4 is not well tolerated. In fact, several studies have correlated overexpression of RECQL4 with the development of malignancies (48–53). We also found that the L638P mutation, which resulted in a stable full-length product with cytoplasmic localization, could not fully rescue the Recql4 deletion.…”

Section: Discussionmentioning

confidence: 99%

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Rothmund-Thomson Syndrome-like RECQL4 truncating mutations cause a haploinsufficient low bone mass phenotype in mice

Castillo-Tandazo

Frazier

Sims

et al. 2020

Preprint

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Rothmund-Thomson Syndrome (RTS) is an autosomal recessive disorder characterized by poikiloderma, sparse or absent hair, and defects in the skeletal system such as bone hypoplasia, short stature, low bone mass, and an increased incidence of osteosarcoma. RTS type 2 patients typically present with germline compound bi-allelic protein-truncating mutations of RECQL4. As existing murine models predominantly employ Recql4 null alleles, we have here attempted to more accurately model the mutational spectrum of RTS by generating mice with patient-mimicking truncating Recql4 mutations. We found that truncating mutations impaired stability and subcellular localization of RECQL4, which translated to a homozygous embryonic lethality and haploinsufficient low bone mass and reduced cortical bone thickness phenotypes. Combination of a truncating mutation with a conditional Recql4 null allele demonstrated that these defects were intrinsic to the osteoblast lineage. However, the truncating mutations did not promote tumorigenesis, even after exposure to irradiation. We also utilized murine Recql4 null cells to assess the impact of a wider range of human RECQL4 mutations using an in vitro complementation assay. We found differential effects of distinct RECQL4 mutations. While some created unstable protein products, others altered subcellular localization of the protein. Interestingly, the severity of the phenotypes correlated with the extent of protein truncation. Collectively, our results reveal that truncating RECQL4 mutations lead to the development of an osteoporosis-like phenotype through defects in early osteoblast progenitors in mice and identify RECQL4 gene dosage as a novel regulator of bone mass.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Rothmund-Thomson Syndrome-like RECQL4 truncating mutations cause a haploinsufficient low bone mass phenotype in mice

Castillo-Tandazo

Frazier

Sims

et al. 2020

Preprint

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“…One reported that RECQL4 drives cisplatin resistance by activating an AKT-YB1-MDR1 signaling pathway 28 . The other study showed that increased RECQL4 expression may predict poor prognosis in GC patients 29 . In GC patients, RECQL4 seems to be associated with treatment resistance, and EGC harboring the RECQL4 variant was associated with non-MGC development.…”

Section: Discussionmentioning

confidence: 95%

Somatic alterations and mutational burden are potential predictive factors for metachronous development of early gastric cancer

Sakuta

Sasaki

Abe

et al. 2020

Sci Rep

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The risk of developing metachronous gastric cancer (MGC) following curative endoscopic submucosal dissection (ESD) of early gastric cancer (EGC) remains even after eradicating Helicobacter pylori (HP) successfully. We screened initial EGC and adjacent non-cancerous mucosa ESD-resected specimens for somatic variants of 409 cancer-related genes, assessing their mutational burden (MB) to predict molecular markers for metachronous post-ESD development. We compared variants between ten patients diagnosed with MGC more than 3 years after ESD and ten age-matched patients who did not have MGC developments after successful HP eradication. We found no significant background differences between the two groups. In adjacent non-cancerous mucosa, the MB tended to be higher in the patients with metachronous developments than in the others. Somatic genomic alterations of RECQL4, JAK3, ARID1A, and MAGI1 genes were significantly associated with MGC development. The criteria including both the MB and their variants, which had potential significant values for predicting MGC. In conclusion, combined of assessing specific somatic variants and MB may be useful for predicting MGC development. This study included a limited number of subjects; however, our novel findings may encourage further exploration of the significance of the molecular features of EGC that predict MGC development, thereby promoting focused follow-up strategies and helping elucidate the mechanisms.

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“…For example, in clinical tissue samples of breast cancer, high levels of RECQL4 protein were significantly associated with aggressive tumor behavior, including lymph node positivity, larger tumor size, HER2 overexpression, ER-negativity, triple-negative phenotypes, and poor survival 22 , and shRNA-mediated RECQL4 suppression in MDA-MB453 breast cancer cells significantly inhibited in vitro clonogenic survival and in vivo tumorigenicity 24 . Higher RECQL4 expression was observed in gastric cancers, and RECQL4 protein levels were associated with poor survival of gastric cancer patients 21 , 26 . The expression of RECQL4 mRNA in hepatocellular carcinoma (HCC) tissues was significantly higher compared with adjacent normal liver tissues; HCC patients with higher levels of RECQL4 expression exhibited significantly shorter disease-free survival and overall survival times compared with those with low levels of expression 23 .…”

Section: Discussionmentioning

confidence: 95%

RECQL4 regulates DNA damage response and redox homeostasis in esophageal cancer

Lyu

Hao

et al. 2021

Cancer Biol. Med.

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Overexpression of RECQL4 is associated with poor prognosis in patients with gastric cancer

Cited by 12 publications

References 24 publications

Rothmund-Thomson Syndrome-like RECQL4 truncating mutations cause a haploinsufficient low bone mass phenotype in mice

Rothmund-Thomson Syndrome-like RECQL4 truncating mutations cause a haploinsufficient low bone mass phenotype in mice

Somatic alterations and mutational burden are potential predictive factors for metachronous development of early gastric cancer

RECQL4 regulates DNA damage response and redox homeostasis in esophageal cancer

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