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Cardiac fibrosis is a common feature of chronic heart failure. Iroquois homeobox (IRX) family of transcription factors plays important roles in heart development; however, the role of IRX2 in cardiac fibrosis has not been clarified. Here we report that IRX2 expression is significantly upregulated in the fibrotic hearts. Increased IRX2 expression is mainly derived from cardiac fibroblast (CF) during the angiotensin II (Ang II)-induced fibrotic response. Using two CF-specific Irx2-knockout mouse models, we show that deletion of Irx2 in CFs protect against pathological fibrotic remodelling and improve cardiac function in male mice. In contrast, Irx2 gain of function in CFs exaggerate fibrotic remodelling. Mechanistically, we find that IRX2 directly binds to the promoter of the early growth response factor 1 (EGR1) and subsequently initiates the transcription of several fibrosis-related genes. Our study provides evidence that IRX2 regulates the EGR1 pathway upon Ang II stimulation and drives cardiac fibrosis., (© 2023. Springer Nature Limited.)

Gastric cancer is one of the most frequent cancers, and it ranks the third most common cancer in China. The most recently caudal-related homeobox transcription factor 2 (CDX2) is expressed in a large number of human gastrointestinal cancers. In addition, gastric epithelial cell mutations in CDX2 result in tumor promotion, which is characterized by cellular drug resistance and a high proclivity for developing cancer. A series of publications over the past years suggests a mechanism by which CDX2 overexpression results in multidrug resistance. CDX2 appears to forward control regenerating IV and the multidrug resistance 1 expression signaling pathway for regulation of cell drug resistance.

Aim: To explore the role of CDX2 in the multi-drug resistance (MDR) process of gastric cancer in vitro and in vivo., Methods: A cisplatin-resistant gastric cancer cell line with stable downregulation of CDX2 was established. mRNA and protein expression levels of CDX2, survivin, cyclin D1, and c-Myc were detected by western blotting and semi-quantitative reverse-transcriptase polymerase chain reaction (RT-PCR). The influence of downregulation of CDX2 on MDR was assessed by measuring IC50 of SGC7901/DDP cells to cisplatin, doxorubicin, and 5-fluorouracil, rate of doxorubicin efflux, apoptosis, and cell cycle progression detected by flow cytometry. In addition, we determined the in vivo effects of CDX2 small interfering RNA (siRNA) on tumor size, and apoptotic cells in tumor tissues were detected by deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling and hematoxylin and eosin staining., Results: CDX2 siRNA led to downregulation of endogenous CDX2 mRNA (0.31 ± 0.05 vs 1.10 ± 0.51, 0.31 ± 0.05 vs 1.05 ± 0.21, P = 0.003) and protein (0.12 ± 0.08 vs 0.51 ± 0.07, 0.12 ± 0.08 vs 0.55 ± 0.16, P = 2.57 × 10(-4)) expression. It significantly promoted the sensitivity of SGC7901/DDP cells to cisplatin (0.12 ± 0.05 vs 0.33 ± 0.08, 0.12 ± 0.05 vs 0.39 ± 0.15, P = 0.001), doxorubicin (0.52 ± 0.13 vs 4.11 ± 1.25, 0.52 ± 0.13 vs 4.05 ± 1.44, P = 2.81 × 10(-4)), and 5-fluorouracil (0.82 ± 0.13 vs 2.81 ± 0.51, 0.82 ± 0.13 vs 3.28 ± 1.03, P = 1.71 × 10(-4)). Flow cytometry confirmed that the percentage of apoptotic cells increased after CDX2 downregulation (32.15% ± 2.15% vs 17.63% ± 3.16%, 32.15% ± 2.15% vs 19.3% ± 2.25%, P = 1.73 × 10(-6)). This notion was further supported by the observation that downregulation of CDX2 blocked entry into the S-phase of the cell cycle (31.53% ± 3.78% vs 65.05% ± 7.25%, 31.53% ± 3.78% vs 62.27% ± 5.02%, P = 7.55 × 10(-7)). Furthermore, downregulation of CDX2 significantly increased intracellular accumulation of doxorubicin (0.21 ± 0.06 vs 0.41 ± 0.11, 0.21 ± 0.06 vs 0.40 ± 0.08, P = 0.003). In molecular studies, semiquantitative RT-PCR and western blotting revealed that CDX2 downregulation could inhibit expression of c-Myc, survivin and cyclin D1., Conclusion: CDX2 may be involved in regulating multiple signaling pathways in reversing MDR, suggesting that CDX2 may represent a novel target for gastric cancer therapy.

Cdx2 is a homeobox domain-containing transcription factor that is important in the development and differentiation of the intestinal cells, and served as a potential biomarker of tumor progression in early intestinal-type gastric cancer. However, its prognostic value and significance in gastric cancer remain controversial. A meta-analysis based on published studies was performed to obtain an accurate evaluation of the association between the presence of Cdx2-positive in clinical samples and clinical outcome. A total of 13 eligible retrospective cohort studies with 1513 patients were included. Cdx2-positive cases were significantly associated with higher male-to-female ratio (RR=1.27, 95% CI: 1.17-1.38, P<0.00001 fixed-effect), lower (I+II) clinical stage (RR=1.63, 95% CI: 1.42-1.87, P<0.00001 fixed-effect), better histologic differentiation (RR=1.54, 95% CI: 1.34-1.76, P<0.00001 fixed-effect), and lower rate of vascular invasion (RR=1.23, 95% CI: 1.08-1.41, P=0.002 fixed-effect) and lymph node metastasis (RR=1.52, 95% CI: 1.33-1.73, P<0.00001 fixed-effect), as well as higher 5-year survival rate (HR=2.22, 95% CI: 1.78-2.75, P<0.00001 fixed-effect). However, the presence of Cdx2 was not associated with tumor size. In summary, Cdx2 is a prognostic factor in gastric cancer, which acts as a marker of good outcome in patients with gastric cancer. Further clinical studies are needed to confirm the role of Cdx2 in clinical practice.