HMGA1 in cancer: Cancer classification by location

Abstract The high mobility group A1 (HMGA1) gene plays an important role in numerous malignant cancers. HMGA1 is an oncofoetal gene, and we have a certain understanding of the biological function of HMGA1 based on its activities in various neoplasms. As an architectural transcription factor, HMGA1 remodels the chromatin structure and promotes the interaction between transcriptional regulatory proteins and DNA in different cancers. Through analysis of the molecular mechanism of HMGA1 and clinical studies, emerging evidence indicates that HMGA1 promotes the occurrence and metastasis of cancer. Within a similar location or the same genetic background, the function and role of HMGA1 may have certain similarities. In this paper, to characterize HMGA1 comprehensively, research on various types of tumours is discussed to further understanding of the function and mechanism of HMGA1. The findings provide a more reliable basis for classifying HMGA1 function according to the tumour location. In this review, we summarize recent studies related to HMGA1, including its structure and oncogenic properties, its major functions in each cancer, its upstream and downstream regulation associated with the tumourigenesis and metastasis of cancer, and its potential as a biomarker for clinical diagnosis of cancer.

evidence of elevated HMGA1 expression in malignant cancer, 4,5 regardless of where the neoplasms originated (Table 1), including in epithelial cancers such as breast cancer, 6 lung cancer, 7,8 colorectal cancer 9,10 and uterine cancer, 11 and mesenchymal tumours such as lipoma/liposarcoma, 12 glioma/glioblastoma, 13 fibroma/fibrosarcoma, 14 leiomyoma 15 and osteosarcoma. 16 Collectively, these studies reveal that HMGA1 has an important role in tumourigenesis and tumour progression and that the expression level of HMGA1 negatively correlates with clinical prognosis.
As HMGA1 is overexpressed in embryonic tissues, comprehending the role of HMGA1 in cancer is essential for our understanding of HMGA1-mediated tumourigenesis. HMGA1 functions as an oncogene through transcriptional regulation and protein-and-protein interaction. For example, in breast cancer, the expression of HMGA1 protein level indicates the adverse outcome of clinical prognosis.
Zhou et al also found that miR-625 suppresses cell migration and proliferation by decreasing HMGA1 protein expression. 17 Overexpression of HMGA1 is correlated with human epidermal growth factor receptor 2 (HER2) and studies show that TGF-β1 induces HMGA1 expression to promote breast cancer. 18 Early studies show that HMGA1 research in colorectal cancer focused on overexpression leading to a worse clinical prognosis. 19 Nearly 5 years of research shows that HMGA1 promotes colorectal cancer development, primarily through transcriptional regulation of such targets as the Wnt signalling pathway, 20 miR-137 21 and miR-214. 22 The rise of metabolomics in recent years has also observed that HMGA1 can increase glucose uptake, promote aerobic glycolysis and promote the development of colorectal cancer. 10,23 Additionally, in HMGA1 transgenic mice, the faecal metabolome can be used as a non-invasive diagnostic marker of early colorectal cancer. 24 In this article, we discuss the current findings on HMGA1 in tumours as well as recent progress in characterizing the molecular mechanism and function of HMGA1 in the tumourigenesis and malignant progression of numerous cancers. We hope this review will provide a stronger understanding of this small but important oncogene and will inform future studies aimed towards the development of targeted therapy and biomarkers for clinical diagnosis.

| CLINICAL PROGNOSIS
In all of the literature, HMGA1 is an oncogene in numerous cancers.
In this paper, we review cancers classified by location and consider Overall, it appears that HMGA1 has an important role in cancer, that HMGA1 expression is increased in cancer, and that elevated HMGA1 expression serves as a predictor of poor clinical prognosis.
In the following review, we summarize the particular role of HMGA1 in each cancer type.

| HEAD AND NECK CANCER
According to recent findings, HMGA1 is a potential biomarker for clinical diagnosis in head and neck cancer. Relevant findings primarily focused on pituitary tumours, named for blastoma tumours and thyroid tumours, and we summarize the results for these types of cancer ( Figure 1).  40 while it is interesting that HMGA1 expression is significantly correlated with glioblastoma stem cells (GSCs). 41 One potential mechanism is that HMGA1 is regulated by miR296-5p, but HMGA1 can promote the transcription of SOX2 and thus promote the maintenance of GSCs. 42 Another article reported that IGF2BP2 and DHX9 bind to each other and then promote HMGA1-mediated modulation of GSC responses to hypoxic stress. 43 HMGA1 maintained the GSC regulatory property and led to temozolomide resistance. 13 In medulloblastomas, it has been reported that HMGA1 can promote the progression of medulloblastoma by promoting cdc25A expression or inhibiting CRMP1 expression. 44,45 In retinoblastomas, HMGA1 expression is correlated with clinical prognosis 46 through the same mechanism of RB/E2F1 deregulation by HMGA1. 47 In neuroblastoma, HMGA1 has been reported as a biomarker for diagnosis and prognosis. 48  factor N-Myc. 49 Giannini et al revealed that MYCN activated a luciferase reporter expressing the HMGA1 promoter, which contains the first three transcription factor binding sites. 48 In thyroid cancer, high HMGA1 expression can be used as a diagnostic marker of thyroid follicular cancer to distinguish between nodular thyroid and thyroid cancer. 29 It was reported that HMGA1 has a vital role in thyroid tissue through inhibition of p53 50 and HAND1 51 and induction of TGF-β1 52 and S100A13. 53 The HMGA1P6 and HMGA1P7 also functions in promoting the malignant progression of thyroid cancer. 54

| TH ORACIC CAN CE R
In thoracic cancer, the studies focused primarily on lung cancer and breast cancer. These findings confirmed that HMGA1 could be used as a diagnostic and prognostic biomarker. Research on lung cancer primarily concerns NSCLC, while other research is focused on breast cancer. In this section, we expand on the findings for lung cancer and breast cancer ( Figure 2).
In NSCLC, using the protein levels or the circulating blood, expression level of HMGA1 as a biomarker for the diagnosis of NSCLC 30 has been studied. The association of SIRT1 expression with HMGA1 expression can be used as a predictor of the prognosis and progression of NSCLC. 55 The level of miR-222 is directly increased by HMGA1 and miR-222 led to an obvious increase in p-Akt levels by inhibiting PPP2R2A, thereby promoting the progression of NSCLC. 56  In colorectal cancer, HMGA1 protein expression in 81 paired tumour tissues and matched, adjacent, non-malignant tissues indicated that HMGA1 is associated with the tumours, especially advanced tumours and lymph node metastases. 9 Another paper showed that in smaller sized (<2 cm) invasive tumours, high HMGA1 expression can increase lymph node metastasis. 19 The faecal metabolome reveals that the expression of the HMGA1 protein is associated with abnormal proliferation in the Hmga1 transgenic mouse intestinal epithelium. This finding is notable because faecal metabolomic analysis can serve as a non-invasive screening tool in the early precursor lesions of colorectal cancer. 24 In the regulation of metabolites, HMGA1 contributes to CRC by inducing fatty acid synthesis and aerobic glycolysis. 10 75 Another paper shows that HMGA1, a predictive marker in hepatocellular carcinoma, is involved intrahepatic metastasis, rather than non-intrahepatic metastasis. 76 There is only one paper on cholangiocarcinoma. Studies show that HMGA1 enhances tumourigenicity and confers resistance to therapy. This paper indicates that HMGA1 promotes colony formation, cell proliferation and resistance to gemcitabine treatment. 77 The quantitative immunohistochemical analysis in HMGA1 transgenic mice aged 5, 11 and 15 months showed that HMGA1 expression is significantly increased in pancreatic intraepithelial neoplasia. 78 HMGA1 serves as a potential diagnostic molecular marker in intraductal papillary mucinous tumours and pancreatic duct cell carcinomas. 79  Based on the preclinical models of drug resistance, chemosensitivity is increased when HMGA1 expression is suppressed, 83 and HMGA1 promotes the chemoresistance of pancreatic carcinoma to gemcitabine. 84 Studies indicate that the PI3-K/Akt pathway has an important role in the specifics of HMGA1 mediated chemoresistance. 85 Li et al report that metformin up-regulated the expression of miRNA, such as let-7c, miR-26a and miR-192, in a dose-dependent manner.
These miRNAs can inhibit pancreatic cancer proliferation. One of these miRNAs, miR-26a directly targets HMGA1 to inhibit pancreatic cancer progression. Therefore, we can conclude that metformin has a role in the treatment pancreatic cancer. 86

| REPRODUCTIVE SYSTEM CANCER
There are many papers that reveal that HMGA1 induces malignant progression and serves as a potential clinical biomarker in reproductive system cancer. PCa is the most investigated cancer in the male genitourinary system, while in the female reproductive system, ovarian carcinoma, uterine cancer, cervical cancer and endometrial cancer studies have been reported in recent decades. We review these studies individually (Figure 4).
In PCa, HMGA1 has been shown to be associated with the nuclear matrix. In examining the HMGA1 protein level during the progression from normal to prostate neoplasia in HMGA1 transgenic mice, the data show that HMGA1 expression is correlated with malignant properties in PCa. 34 Because the prostate belongs to the male internal genital organ and it can be influenced by androgen, HMGA1 could transform PCa cells from androgen-sensitive to androgen-insensitive and could play a vital role in the cell proliferation of androgen-independent PCa cells. 87 It is well known that HMGA1 is highly expressed in embryogenesis, as well as in most malignant neoplasms, and it has been found in post-pubertal testicular germ cell tumours, including in seminomas and embryonal carcinomas. Chieffi et al reported that HMGA1 has high expression in testicular seminomas. 88  Other studies on small molecules or drugs targeting HMGA1 are few, and more studies are needed for further discovery.

ACKNOWLEDGEMENTS
This study was supported by the National Natural Science Foundation of China (no. 31700778) and the China Postdoctoral Science Foundation funded project (no. 7131702818). We thank Wiley for the English language editing of the article.

DISCLOSURE
No potential conflicts of interest were disclosed.

AUTHORS' CONTRI BUTION
YW, LG conceptualized and designed the study; also written, reviewed and revised the manuscript. YW, LH developed the methodology. YW, LH, YZ analysed and interpreted the data.
LG supervised the study.