G-quadruplex formation within the promoter region of HSPB2 and its effect on transcription.

G-rich sequences in DNA and RNA tend to fold into stable secondary structures called G-quadruplexes. Except for the telomere region, G-quadruplex-forming sequences are widely present in gene promoters and have been implicated in transcriptional regulation. Single nucleotide polymorphisms (SNPs) can disrupt the G-quadruplex structure of a gene promoter. In this study, we confirmed the promoter of HSPB2, a cancer-related gene, tends to form an unusual DNA secondary structure. The dual luciferase assay revealed that the SNP rs2234704 in the HSPB2 promoter with a single G > A mutation increased the transcriptional activity of the HSPB2 promoter. Circular dichroism and native PAGE revealed that the G-rich strand of the DNA in this promoter preferred to form a parallel G-quadruplex, which could be destabilized by the SNP rs2234704 (G > A) mutation. Furthermore, we found that the SNP rs2234704 (G > A) greatly increased and influenced the overexpression of HSPB2 in breast cancer samples. These results suggest SNP rs2234704 (G > A) may play a role in the occurrence of breast cancer by destroying the G-quadruplex structure and promoting the expression of HSPB2.

A novel copper chelator for the suppression of colorectal cancer.

Copper ions play a crucial role in the progression of cancers. Tumor tissue is rich in copper ions, and copper chelators could potentially scavenge these copper ions and thus exert an antitumor effect. In this study, we report the synthesis of a novel thieno[3,2-c]pyridine compound we have called "JYFY-001" that can act as the copper chelator thanks to the inclusion of an N-(pyridin-2-yl)acetamide moiety that targets copper ions. JYFY-001 potently inhibited cancer proliferation, inducing cell apoptosis and impairing the extracellular acidification rate and oxygen consumption rate of colorectal cancer (CRC) cells. JYFY-001 also inhibited the growth of a CRC-transplanted tumor in a dose-dependent manner, inducing apoptosis of the tumor cells and promoting the infiltration of lymphocytes in the CRC-transplanted tumor tissues. JYFY-001 also enhanced the antitumor effects of the programmed cell death protein 1 (PD-1) inhibitor. The relatively benign nature of JYFY-001 was demonstrated by the effect on normal cell viability and acute toxicity tests in mice. Our findings suggest that JYFY-001 is a prospective copper chelator to be used as a targeted drug and a synergist of immunotherapy for CRC treatments.

Tumor cell-secreted exosomal miR-22-3p inhibits transgelin and induces vascular abnormalization to promote tumor budding.

Tumor budding (TB) is considered a histomorphological marker of poor prognosis in patients with breast cancer (BC). Tumor vasculature is disordered and unstable in BC, which causes restricted drug delivery, hypoxia, and tumor metastasis. Traditional anti-angiogenic treatments cause extreme hypoxia, increased invasion, metastasis, and drug resistance due to blood vessel rarefaction or regression. Therefore, the application of anti-angiogenic strategies for vascular normalization in tumors is crucial to improve therapeutic efficacy in BC. In the present study, we found that transgelin (TAGLN) promoted the normalization of tumor vessels by regulating the structure and function of endothelial cells, and knockout of TAGLN in tumor-bearing mice resulted in tumor vessel abnormalization, an increase in epithelial-mesenchymal transition characteristics of tumor cells, and promotion of TB. Moreover, BC cells secrete exosomal miR-22-3p that mediates tumor vessel abnormalization by inhibiting TAGLN. We demonstrated for the first time that TAGLN plays an essential role in tumor vessel normalization, and thus it impairs TB and metastasis. Additionally, the findings of this study indicate that exosomal miR-22-3p is a potential therapeutic target for BC.