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. 2020 Feb 5;11(2):92.
doi: 10.1038/s41419-020-2272-z.

TfR1 binding with H-ferritin nanocarrier achieves prognostic diagnosis and enhances the therapeutic efficacy in clinical gastric cancer

Xiaojing Cheng #  1 , Kelong Fan #  2 , Lin Wang #  1   3   4 , Xiangji Ying  3 , Andrew J Sanders  5 , Ting Guo  1 , Xiaofang Xing  1 , Meng Zhou  2 , Hong Du  1 , Ying Hu  6 , Huirong Ding  7 , Ziyu Li  3 , Xianzi Wen  1 , Wenguo Jiang  8 , Xiyun Yan  9 , Jiafu Ji  10   11
Affiliations

TfR1 binding with H-ferritin nanocarrier achieves prognostic diagnosis and enhances the therapeutic efficacy in clinical gastric cancer

Xiaojing Cheng et al. Cell Death Dis. .

Erratum in

Abstract

H-ferritin (HFn) nanocarrier is emerging as a promising theranostic platform for tumor diagnosis and therapy, which can specifically target tumor cells via binding transferrin receptor 1 (TfR1). This led us to investigate the therapeutic function of TfR1 in GC. The clinical significance of TfR1 was assessed in 178 GC tissues by using a magneto-HFn nanoparticle-based immunohistochemistry method. The therapeutic effects of doxorubicin-loaded HFn nanocarriers (HFn-Dox) were evaluated on TfR1-positive GC patient-derived xenograft (GC-PDX) models. The biological function of TfR1 was investigated through in vitro and in vivo assays. TfR1 was upregulated (73.03%) in GC tissues, and reversely correlated with patient outcome. TfR1-negative sorted cells exhibited tumor-initiating features, which enhanced tumor formation and migration/invasion, whereas TfR1-positive sorted cells showed significant proliferation ability. Knockout of TfR1 in GC cells also enhanced cell invasion. TfR1-deficient cells displayed immune escape by upregulating PD-L1, CXCL9, and CXCL10, when disposed with IFN-γ. Western blot results demonstrated that TfR1-knockout GC cells upregulated Akt and STAT3 signaling. Moreover, in TfR1-positive GC-PDX models, the HFn-Dox group significantly inhibited tumor growth, and increased mouse survival, compared with that of free-Dox group. TfR1 could be a potential prognostic and therapeutic biomarker for GC: (i) TfR1 reversely correlated with patient outcome, and its negative cells possessed tumor-aggressive features; (ii) TfR1-positive cells can be killed by HFn drug nanocarrier. Given the heterogeneity of GC, HFn drug nanocarrier combined with other therapies toward TfR1-negative cells (such as small molecules or immunotherapy) will be a new option for GC treatment.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1. TfR1 protein expression in GC patients reversely correlated with poor prognosis.
a Different staining scores with M-HFn nanoparticles detecting TfR1 in GC tissues by IHC, scale bars: 50 µm. b Expression level of TfR1 protein in GC and their (or matched) adjacent noncancerous tissues. c TfR1 mRNA expression was significantly upregulated in GC tissues compared with adjacent normal mucosa in GES63089 and 13861 from GEO datasheets, respectively. d Ratio (T/N) of TfR1 mRNA expression in 11 paired primary GC patients, which was determined by qPCR (lower panel). Their expression levels were normalized by an internal control (GAPDH). e IHC staining that indicated high TfR1 protein expression was significantly associated with location of GC. f Kaplan–Meier survival analysis of OS obtained from public gene expression datasets. g Kaplan–Meier analysis of 5-year survival with low vs. high TfR1 protein expression status (left); Kaplan–Meier survival analysis of DFS with low vs. high TfR1 protein expression status (right). *P < 0.05; **P < 0.01; ****P < 0.0001.
Fig. 2
Fig. 2. HFn-encapsulated Dox superiorly killed GC-PDX tumors.
a H&E staining showed the similar histology of the patients and their corresponding PDX-derived tumors. b Tumor growth curves for different mouse groups were indicated. Red arrows: dose injection for every 5 days. c Mouse survival curves in different groups with Kaplan–Meier analysis. d Body weight changes in GC-PDX model. Red arrows: dose injection every 5 days. e Detection of proliferative and apoptotic cells in different groups after drug treatment. Scale bars, (e left two panels) 100 µm; (e right panel) 50 µm.
Fig. 3
Fig. 3. GC cells with the absence of TfR1 possess tumor-initiating like properties through in vitro and in vivo assays.
a RNA-seq profiles for sorted TfR1-negative and -positive cells were analyzed. Significant signaling pathway (left panel) and volcano plot illustrated the differentially expressed genes between TfR1-negative and -positive cells (right panel, fold change > 2.0 or <2.0; Q value < 0.05). Blue, green, and red colors indicated various genes belonging to different groups of cell processes. b TfR1 was overexpressed in six GC cells (BGC823, SGC7901, AGS, HGC27, N87, and GES1). c–e Absence of TfR1 promoted cell migration, invasion, and colonogenicity by wound-healing assay, Boyden chamber invasion assay, and colony formation assay. Scale bar: 100 µm. f Analysis of TfR1 sorted ± cell tumorigenity following transplantation with different numbers of cells into NOD/SCID mice. g Sox2, Nanog, Oct4, and CACNA2D1 mRNA relative expression was determined by qPCR. Their expression levels were normalized by an internal control (GAPDH). h TfR1-positive sorted cells showed obviously cell proliferation ability detected by real-time RTCA instrument. *P < 0.05; **P < 0.01, ***P < 0.001.
Fig. 4
Fig. 4. Migration/invasion of TfR1-negative cells was inhibited by the antibody toward CACNA2D1.
a IF analysis indicated TfR1-sorted negative and positive cells co-expressing CACNA2D1 and CD44. b TfR1-sorted negative and positive cells were assayed for their migration/invasion abilities, with 17 μg/ml 1B50-1, and their matched mouse IgG antibody, using a Boyden chamber assay. Bars represent the mean and SD for three independent experiments. Scale bars, 10 µm; *P < 0.05; **P < 0.01. Scale bars, 2.5 µm. SD standard deviation.
Fig. 5
Fig. 5. TfR1-knockout cells displayed malignant properties and responded to IFN-γ treatment.
a GSEA plot based on RNA-seq (upper panel) or TCGA data (lower panel) indicated TfR1-negative cells correlated with developmental and immune deficiency. b TfR1-knockout cells were identified by flow cytometry analysis. c TfR1-knockout GC cells showed high invasion ability evaluated by RTCA real-time analysis instrument. d Knockout of TfR1 increased cell colonogenicity. e PD-L1, CXCL9, and CXCL10 mRNA level was enhanced in TfR1-knockout cells stimulated with IFN-γ (100 ng/ml) for 24 h. f The correlation of EMT- related markers, STAT3/AKT signaling with TfR1, were detected by Western blot. NES normalized enrichment score. *P < 0.05; **P < 0.01; ***P < 0.001.
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