As a member of the HMGA protein family, high mobility group A2 (HMGA2) is a chromatin-related nonhistone nuclear binding protein widely found in eukaryotes [1], [2]. HMGA2 exhibits high mobility in polyacrylamide gel electrophoresis (PAGE) [3]. Although it is abundantly expressed during embryogenesis, its expression remains at low levels or is undetectable in normal adult tissues, suggesting that HMGA2 is an important cell growth and differentiation regulator during embryonic development [4], [5]. However, HMGA2 lacks transcriptional activity [6] and instead, binds to the DNA of the target gene through its specific protein structure in the AT-hook region to alter the chromatin structures in the location of the target gene. Consequently, this results in DNA deformation events, such as stretching and curling, which, in turn, regulate the transcription and expression of the target gene. Therefore, HMGA2 is also known as a structural transcription factor [2], [7].

HMGA2 is currently considered a new oncogene [8], [9]. Previous studies have shown that abnormal HMGA2 protein expression is associated with the occurrence of many malignancies of epithelial tissue, such as oral squamous cell carcinoma [10], gastric cancer [11], colorectal cancer [12], pancreatic cancer [13], ovarian cancer [14], breast cancer [15], thyroid cancer [16], gallbladder cancer [17], nasopharyngeal carcinoma [18], and nonsmall cell lung cancer [19]. The overall patient survival with a high level of HMGA2-mRNA expression is lower than that of patients with a low level of HMGA2-mRNA expression. As a structural transcription factor, HMGA2′s mechanism of action tumorigenesis and the development of distant metastases is exerted mainly through the transcription and activation of the targeted genes [20]. This process results in the appearance of epithelial–mesenchymal transition (EMT), which enables cancer cells to acquire characteristics of stem cells that promote self-renewal and infinite proliferation and ultimately improve the invasiveness and migration capabilities of tumor cells [21], [22], [23]. Therefore, we speculate that through the regulation of gene transcription during tumorigenesis and metastasis development, HMGA2 can alter the tumor cell functions, enabling cell invasion and metasisization. The adhesion molecule CD44, a cell surface transmembrane glycoprotein, is a marker used in the identification of cell subpopulations with cancer stem cell (CSC) properties in breast, colorectal, and gastric cancer [24], [25], [26], [27]. OCT4, a nuclear transcription factor of the POU homeodomain family is critical for the formation, self-renewal, and differentiation of pluripotent stem cells in the mammalian embryo. Thus, it plays an essential role in controlling the early stages of mammalian embryogenesis and is another marker that has been used in CSC detection. OCT4 may be detected in different types of CSCs in tumor cell clusters [28]. Since it is generally accepted that high CD44 and OCT4 expression levels are associated with the pluripotent properties of stem cells, CD44 and OCT4 are commonly used as cancer stem cell markers in cancer research [29], [30].

In this study, the biological characteristics of gastric cancer cells, such as cell proliferation, invasiveness, and migration capabilities before and after overexpression of HMGA2, were evaluated using approaches in genetic engineering and molecular biology. The effects of HMGA2 on stem cell acquisition of tumor cells were also evaluated by examining the expression of CD44 and OCT4 in gastric cancer cells. This study aims to elucidate HMGA2′s role in the occurrence and metastasis of gastric cancer and to provide theoretical support for research on the metastasis mechanism and potential targeted treatment strategies of gastric cancer.