Challenges of deciphering gastric cancer heterogeneity

Hudler, Petra

doi:10.3748/wjg.v21.i37.10510

Cited by 70 publications

(54 citation statements)

References 201 publications

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“…These findings support the role of the DCLK1-based miRNA signature in determining a prognosis for colon cancer patients. We note that a number of groups have demonstrated that DCLK1 expression can predict survival in colon cancer [9, 35]. Although we found similar significant results using DCLK1 gene expression data from the TCGA colon cancer RNA-seq dataset (Figure 7), the DCLK1-based miRNA signature was able to stratify risk with much greater efficiency.…”

Section: Discussionsupporting

confidence: 76%

Survival of Patients with Gastrointestinal Cancers Can Be Predicted by a Surrogate microRNA Signature for Cancer Stem–like Cells Marked by DCLK1 Kinase

Weygant

et al. 2016

Cancer Research

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DCLK1 is a gastrointestinal (GI) tuft cell kinase that has been investigated as a biomarker of cancer stem-like cells in colon and pancreatic cancers. However, its utility as a biomarker may be limited in principle by signal instability and dilution in heterogeneous tumors, where the proliferation of diverse tumor cell lineages obscures the direct measurement of DCLK1 activity. To address this issue, we explored the definition of a microRNA signature as a surrogate biomarker for DCLK1 in cancer stem-like cells. Utilizing RNA/miRNA sequencing datasets from the Cancer Genome Atlas, we identified a surrogate 15-miRNA expression signature for DCLK1 activity across several GI cancers, including colon, pancreatic and stomach cancers. Notably, Cox regression and Kaplan-Meier analysis demonstrated that this signature could predict the survival of patients with these cancers. Moreover, we identified patient subgroups that predicted the clinical utility of this DCLK1 surrogate biomarker. Our findings greatly strengthen the clinical significance for DCLK1 expression across GI cancers. Further, they provide an initial guidepost toward the development of improved prognostic biomarkers or companion biomarkers for DCLK1-targeted therapies to eradicate cancer stem-like cells in these malignancies.

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Section: Discussionsupporting

confidence: 76%

Survival of Patients with Gastrointestinal Cancers Can Be Predicted by a Surrogate microRNA Signature for Cancer Stem–like Cells Marked by DCLK1 Kinase

Weygant

et al. 2016

Cancer Research

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“…GC develops as a biologically heterogeneous disease involving multiple genetic and epigenetic alterations [9, 13, 15, 41]. Aberrant gene expression profiles have been associated with GC progression, prognosis and pathogenesis [9, 13, 15, 41, 42].…”

Section: Discussionmentioning

confidence: 99%

“…Aberrant gene expression profiles have been associated with GC progression, prognosis and pathogenesis [9, 13, 15, 41, 42]. In the present study, gene expression microarray was applied to screen differentially expressed genes in GC tissues.…”

Section: Discussionmentioning

confidence: 99%

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Overexpression of Lymphocyte Antigen 6 Complex, Locus E in Gastric Cancer Promotes Cancer Cell Growth and Metastasis

Chen

et al. 2018

Cell Physiol Biochem

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Background/Aims: Lymphocyte antigen 6 complex, locus E (LY6E) is a member of the lymphostromal cell membrane Ly6 superfamily protein. The present study investigated the clinical significance and potential biological function of LY6E in gastric cancer (GC). Methods: LY6E mRNA and protein expressions in human GC tissues and GC cells were tested. Relationship between LY6E expression and the GC patients’ clinicopathologic characteristics was analyzed. LY6E was silenced by siRNA in the cultured GC cells. Results: The RNA expression microarray profiling assay results demonstrated that LY6E mRNA was significantly increased in multiple human GC tumor tissues. Immunohistochemistry (IHC) staining analysis revealed that 59 of 75 (78.7%) GC specimens were LY6E positive. LY6E over-expression in human GC was correlated with the histology grade, AJCC stage, N classification, lymphatic invasion, and tumor location. Notably, functional LY6E expression was also detected in AGS and other established GC cell lines. LY6E knockdown by targeted-siRNA inhibited AGS cell survival and proliferation. Meanwhile, the LY6E siRNA induced G1-S cell cycle arrest and apoptosis in AGC cells. Additionally, AGC cell migration was also inhibited by LY6E knockdown. Expressions of tumor-suppressing proteins, including PTEN (phosphatase and tensin homolog) and E-Cadherin, were increased in LY6E-silenced AGS cells. Conclusion: LY6E over-expression in GC is potentially required for cancer cell survival, proliferation and migration.

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“…Molecularly-targeted therapy has drawn broad attention recently [8-14]. Identification of novel oncotarget proteins is important for GC diagnosis and treatment [8-11]. …”

Section: Introductionmentioning

confidence: 99%

Inhibition of HHIP Promoter Methylation Suppresses Human Gastric Cancer Cell Proliferation and Migration

Zuo

Qian

et al. 2018

Cell Physiol Biochem

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Background/Aims: Human hedgehog-interacting protein (HHIP) is a negative regulator of the hedgehog (HH) signaling pathway. It is deregulated in gastric cancer. The underlying molecular mechanism of HHIP-induced inhibition of HH signaling remains to be determined. Methods: A lentiviral HHIP expression vector (“LV-HHIP”) was established to exogenously over-express HHIP in gastric cancer cells. HHIP protein and mRNA were tested by Western blotting assay and quantitative real-time PCR assay, respectively. Cell survival was tested by the Cell Counting Kit-8 (CCK-8) assay. Cell proliferation was examined by the BrdU ELISA assay and [H³] Thymidine DNA incorporation assay. Cell invasion and migration were tested by the phagokinetic track assay and the “Transwell” assay. The bisulfite-sequencing PCR was applied to test HHIP promoter methylation. Results: In the established (AGS cell line) and primary human gastric cancer cells, LV-HHIP transfection increased HHIP expression and inhibited cancer cell survival and proliferation as well as cell migration and invasion. Furthermore, LV-HHIP significantly attenuated promoter methylation of the endogenous HHIP gene in AGS cells, causing it upregulation. Inhibition of methylation by 5-aza-dc similarly induced HHIP expression in gastric cancer cells, which inhibited cancer cell proliferation and migration. Conclusions: Our results suggest that inhibition of HHIP promoter methylation can efficiently inhibit human gastric cancer cell proliferation and migration.

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Challenges of deciphering gastric cancer heterogeneity

Cited by 70 publications

References 201 publications

Survival of Patients with Gastrointestinal Cancers Can Be Predicted by a Surrogate microRNA Signature for Cancer Stem–like Cells Marked by DCLK1 Kinase

Survival of Patients with Gastrointestinal Cancers Can Be Predicted by a Surrogate microRNA Signature for Cancer Stem–like Cells Marked by DCLK1 Kinase

Overexpression of Lymphocyte Antigen 6 Complex, Locus E in Gastric Cancer Promotes Cancer Cell Growth and Metastasis

Inhibition of HHIP Promoter Methylation Suppresses Human Gastric Cancer Cell Proliferation and Migration

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