Attenuation of cancer proliferation by suppression of glypican-1 and its pleiotropic effects in neoplastic behavior

Our plain-English summary of Attenuation of cancer proliferation by suppression of glypican-1 and its pleiotropic effects in neoplastic behavior, by F. Cheng, V.C. Hansson, G. Georgolopoulos, et al (Oncotarget, 2023).

The study

• Authors: F. Cheng, V.C. Hansson, G. Georgolopoulos, K. Mani
• Journal: Oncotarget
• Published: 2023;14:219-235
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Glypicans (GPC1-6) are associated with tumorigenic processes and their involvement in neoplastic behavior has been discussed in different cancer types. Here, a cancer-wide GPC expression study, using clinical cancer patient data in The Cancer Genome Atlas, reveals net upregulation of GPC1 and GPC2 in primary solid tumors, whereas GPC3, GPC5 and GPC6 display lowered expression pattern compared to normal tissues. Focusing on GPC1, survival analyses of the clinical cancer patient data reveal statistically significant correlation between high expression of GPC1 and poor prognosis in 10 particular cancer types i.e., bladder urothelial carcinoma, brain lower grade glioma, liver hepatocellular carcinoma, colon adenocarcinoma, kidney renal clear cell carcinoma, lung adenocarcinoma, mesothelioma, ovarian serous cystadenocarcinoma, uterine corpus endometrial carcinoma and uveal melanoma. In vitro studies targeting GPC1 expression by CRISPR/Cas9 or siRNA or treatment with an anti-GPC1 antibody resulted in attenuation of proliferation of cancer cells from bladder carcinoma, glioma and hepatocellular carcinoma patients (T24, U87 and HepG2 cells). Further, overexpression of GPC1 exhibited a significant and negative correlation between GPC1 expression and proliferation of T24 cells. Attempt to reveal the mechanism through which downregulation of GPC1 leads to attenuation of tumor growth using systematic Ingenuity Pathway Analysis indicate that suppression of GPC1 results in ECM-mediated inhibition of specific pro-cancer signaling pathways involving TGF-β and p38 MAPK. Identified differential expression and pleiotropic effects of GPCs in specific cancer types emphasize their potential of as novel diagnostic tools and prognostic factors and open doors for future GPC targeted therapy.

In plain English

This laboratory and database study did not look at asbestos. The authors used public gene-expression and survival data from The Cancer Genome Atlas, covering 33 cancer types including mesothelioma, to study cell-surface proteins called glypicans. GPC1 and GPC2 genes had significantly higher expression in primary solid tumors than in normal tissue; GPC3, GPC5 and GPC6 had lower expression. Higher GPC1 gene expression was statistically associated with poorer survival in 10 cancer types, one of them mesothelioma. The hazard ratios and numbers of patients at risk for each cancer type appear only in figures. In lab-grown bladder (T24), brain glioma (U87) and liver (HepG2) cancer cells, targeting GPC1 with CRISPR/Cas9 cut growth to 59%, 72% and 52% of untreated cells. Silencing GPC1 by a second method also reduced growth. A GPC1 antibody reduced T24 and HepG2 growth to about 75% of untreated cells, with no observed effect on U87 cells. Overexpressing GPC1 raised T24 growth to 140% of untreated or mock-transfected control cells. No mesothelioma cells were tested. The authors proposed a putative mechanism in which lowering GPC1 dampens growth signals involving TGF-beta and p38 MAPK.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Analysis of public cancer gene-expression and survival data (The Cancer Genome Atlas) combined with laboratory cell-culture experiments
• Who was studied: Primary tumor samples and patients with survival data from 33 TCGA cancer types, including mesothelioma (TCGA-MESO). Patient numbers for each cancer type appear only in figures. The study also used three commercial cancer cell lines: T24 bladder carcinoma cells (from an 81-year-old female patient), HepG2 hepatocellular carcinoma cells (from a 15-year-old male patient) and U-87 malignant glioma cells (from a male patient).
• Exposure: No asbestos or fiber exposure was studied. The factor examined was the expression level of the glypican-1 (GPC1) gene. In the cell lines, GPC1 was experimentally reduced (CRISPR/Cas9 knock-out, siRNA knock-down, anti-GPC1 antibody) or increased (overexpression).
• Main results:
  • Across TCGA samples, GPC1 and GPC2 had significantly higher expression in primary solid tumors than in healthy tissues. GPC3, GPC5 and GPC6 had overall lower expression in cancerous tissues.
  • Higher GPC1 expression was statistically significantly associated with poorer patient survival in 10 TCGA cancer types, including mesothelioma (MESO). Hazard ratios with 95% confidence intervals are shown in Figure 2 and numbers at risk in Figure 3, but their values are not in the text.
  • Targeting GPC1 with CRISPR/Cas9 reduced proliferation of T24, U87 and HepG2 cells to 59%, 72% and 52% respectively of untreated controls (N = 5, P less than or equal to 0.01).
  • Knocking down GPC1 with siRNA significantly decreased proliferation in all three cell types compared with cells given a scrambled control (siRNAmock).
  • An anti-GPC1 antibody reduced proliferation of T24 and HepG2 cells to about 75% of that in untreated cells. No effect was observed on U87 cells.
  • Overexpressing GPC1 in T24 bladder carcinoma cells increased proliferation to 140% of that in untreated or Mock cells (N = 5, P less than or equal to 0.001).
  • The authors ran a pathway analysis of 66 genes that differed between GPC1-low and GPC1-high patients in at least 5 cancer types. For GPC1-low patients, it predicted inhibition of regulators including TGF-beta 1, p38 MAPK, AKT, PDGF-BB, interferon-alpha and WNT.
• The authors' conclusion: The authors concluded that their results highlight a putative mechanism in which suppressing GPC1 leads to inhibition, through the extracellular matrix, of growth-promoting factors such as TGF-beta and MAPK. They suggested that GPC1 has potential as a diagnostic tool, a prognostic factor and a target for future cancer therapies.
• Limitations the authors state:
  • The CRISPR/Cas9 knock-out lowered GPC1 protein signal but did not completely eliminate it.
  • The authors note that the exact mechanism by which glypicans are involved in malignant behavior is not known.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Colon cancer.

Medical terms in this study, explained in our Lexicon: Prognosis, Carcinoma, Adenocarcinoma, Lung Adenocarcinoma, Mesothelioma, Targeted Therapy.

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