68Ga-FAPI-04 PET Distinguishes Malignancy from Inflammatory Lesions

Background The 68Ga-labelled FAPI provides new oncology imaging option other than 18F-FDG-PET. However, it's unclear about whether the FAPI-PET distinguishes malignancy from benign lesions. Methods We established an AOM/DSS-induced rat colorectal tumor model. A double PET/CT tracer of 68Ga-FAPI-04 and 18F-FDG was used in the rat colorectal tumor model. Histological examination, immunohistochemistry staining, and radioautography were performed in this study. Results 68Ga-FAPI PET imaging distinguishes neoplasia from inflammatory lesions in an AOM/DSS-induced rat colorectal tumor model, and FAPI accumulation gradually increases along with tumor progression. An inflammatory lesion did not interfere with 68Ga-FAPI PET imaging. Conclusion The 68Ga-FAPI-04 PET distinguishes malignant tumors from inflammatory lesions by detecting FAP in a rat colorectal tumor model, suggesting that 68Ga-FAPI-04 PET is a better diagnostic tool than 18F-FDG PET, at least to colorectal cancer patients.

FBXW11 contributes to stem-cell-like features and liver metastasis through regulating HIC1-mediated SIRT1 transcription in colorectal cancer

Colorectal tumorigenesis is a heterogeneous disease driven by multiple genetic and epigenetic alterations. F-box and WD repeat domain containing 11 (FBXW11) is a member of the F-box protein family that regulates the ubiquitination of key factors associated with tumor growth and aggressiveness. Our study aimed to explore the role of FBXW11 in the development and metastasis of colorectal cancer (CRC). FBXW11 was overexpressed in colorectal tumor tissues and its overexpression was associated with a poor prognosis of CRC patients. The upregulation of FBXW11 not only promoted cell proliferation, invasion, and migration, but also contributed to maintaining stem-cell features in colorectal tumor cells. Further analysis revealed that FBXW11 targeted hypermethylated in cancer 1 (HIC1) and reduced its stability in CRC cells through ubiquitination. Moreover, the expression of sirtuin 1 (SIRT1), a deacetylase in tumor cells was upregulated by FBXW11 via regulating HIC1 expression. The mouse xenograft models of CRC confirmed that FBXW11 knockdown impeded colorectal tumor growth and liver metastasis in vivo. In summary, our study identified FBXW11 as an oncogenic factor that contributed to stem-cell-like properties and liver metastasis in CRC via regulating HIC1-mediated SIRT1 expression. These results provide a rationale for the development of FBXW11-targeting drugs for CRC patients.

Di-2-pyridylketone 4, 4-dimethyl-3-thiosemicarbazone effectively induces human colorectal carcinoma cell apoptosis via mTOR pathway

Background: To investigate the anticancer mechanisms of di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) in human colon cancer cells. Human colorectal carcinoma (HCC) is one of the most commonly diagnosed cancers in both males and females. Current studies have found that iron chelators can be used as novel anticancer drugs; however, the anticancer activity of iron chelators and their target genes in HCC has been rarely reported. Methods: Dp44mT was used to treat two colorectal tumor cell lines, SW480 and HT-29. The proapoptotic effects of different concentrations of Dp44mt were measured using flow cytometry and Hoechst 33258 staining. Ferric ammonium citrate (FAC) was used as an additional iron donor to inhibit the effects of Dp44mT. Apoptosis and DNA damage-related proteins were examined by Western blot analysis. Results: In this study, we found that the iron chelators Dp44mT could induce the apoptosis in two colorectal tumor cell lines SW480 and HT-29, upregulate the expression level of p-histone H2A.X, and inhibit the phosphorylation level of mTOR in a dose-dependent way. Those effects could be reversed by the additional iron donor FAC. Conclusion: These data indicate that iron depletion and/or the presence of iron can modulate the HCC apoptosis progression in vitro, which may be a potential target for future HCC therapy.

AM22 Inhibites the Proliferation of Colorectal Cancer by Targeting CBFB

Our previous studies have revealed the important roles of the non-seed regions of miRNAs in gene regulation, which provided a novel insight in the development of miRNA analogs for cancer therapy. Here, we altered each nucleotide in the non-seed region of miR-34a and obtained novel synthetic miRNA analogs. Among them, AM22 with a base alteration from G to C at the 17th nucleotide of miR-34a, showed extensive anti-proliferative activity against several colorectal tumor cell lines, and achieved effective inhibition of CBFB (core binding factor subunit β) expression. Subsequent investigations demonstrated that AM22 directly targeted CBFB by binding to its 3'-untranslated region (3'-UTR). Inhibition of CBFB showed obvious anti-proliferative activity on HCT-116 and SW620 cells. Furthermore, the anti-proliferative effects of AM22 on these cells were also measured in the xenograft mouse models. In conclusion, this study identified AM22 as a potential anti-tumor miRNA by targeting CBFB, and provided a new design approach for miRNA-based cancer treatment by changing the non-seed region of miRNA.