HMGA1 exacerbates tumor growth through regulating the cell cycle and accelerates migration/invasion via targeting miR-221/222 in cervical cancer

Abstract

High-mobility group AT-hook1 (HMGA1, formerly HMG-I/Y), an architectural transcription factor, participates in a number of tumor biological processes. However, its effect on cervical cancer remains largely indistinct. In this study, we found that HMGA1 was generally overexpressed in cervical cancer tissues and was positively correlated with lymph node metastasis and advanced clinical stage. Via exogenously increasing or decreasing the expression of HMGA1, we showed that HMGA1 affected the proliferation, colony formation, migration and invasion of cervical cancer cells in vitro. Rescue experiments suggested that miR-221/222 could partly reverse HMGA1-mediated migration and invasion processes. Mechanistically, we discovered that HMGA1 accelerated the G1/S phase transition by regulating the expression of cyclin D1 and cyclin E1, which was consistent with the results of the in vivo experiment. Furthermore, we found that HMGA1 regulated the expression of the miR-221/222 cluster at the transcriptional level and that miR-221/222 targeted the 3′UTR of tissue inhibitor of metalloproteinases 3(TIMP3). We propose a fresh perspective that HMGA1 participates in the migration and invasion process via the miR-221/222-TIMP3-MMP2/MMP9 axis in cervical cancer. In summary, our study identified a critical role played by HMGA1 in the progression of cervical cancer and the potential mechanisms by which exerts its effects, suggesting that targeting HMGA1-related pathways could be conducive to the therapies for cervical cancer.

High-mobility group AT-hook 1 promotes cardiac dysfunction in diabetic cardiomyopathy via autophagy inhibition

“…The HMGA1 protein is a structural factor that binds to DNA regions rich in adenine-thymine (A-T), which have no intrinsic transcriptional activity 16 . HMGA1 drives gene transcription by promoting the assembly and stability of higher transcriptional complexes 18 . Previous studies demonstrated that HMGA1 deficiency induces cardiac hypertrophy 19,20 .…”

“…High-mobility family AT-Hook1 (HMGA1) binds to the AT-rich region of DNA 13 . HMGA1 takes part in various fundamental processes at the molecular and cellular level, such as cell cycle progression 14 , embryologic development 15 , neoplastic transformation 16 , differentiation 17 , apoptotic cellular metabolism, and DNA repair 18 . Research has uncovered that cardiac hypertrophy and myelo-lymphoproliferative disorders were observed in mice with HMGA1 haploinsufficiency 19 .…”

LINC00665 enhances tumorigenicity of endometrial carcinoma by interacting with high mobility group AT-hook 1

“…For example, HMGA1 can promote breast cancer angiogenesis via supporting the transcriptional activity of FOXM1 [29]. HMGA1 exacerbates cervical cancer growth via regulating cell cycle and migration/invasion capacity through targeting miR-221/222 [30]. HMGA1 is correlated with breast cancer malignant status [31].…”

Role of miR-221/222 in Tumor Development and the Underlying Mechanism

“…e abnormal high expression of miR-221/222 is involved in various cancers (Table 1), which promotes the malignant proliferation, immune escape, invasion, and metastasis of tumor cells [94]. rough the retrieval and statistics of the databases (including PubMed and Web of Science), the oncogene upregulated with overexpression of miR-221/222, including glioblastoma [31], gastric cancer [32,33], bladder cancer [35], hepatocellular carcinoma [38,39,51,59], lung cancer [36,37], liver cancer [29,51], breast cancer [60][61][62][63], cervical cancer [64,68,95], ovarian cancer [66,69,70], endometrial carcinoma [74], melanoma [75,76], pancreatic cancer [77], thyroid cancer [78,79], multiple myeloma [80], chronic lymphocytic leukemia [79], oral carcinoma [82], retinoblastoma [83,96], nasopharyngeal carcinoma [84], and prostate carcinoma [85], was summarized. However, the upregulation of miR-221/222, also referred to as tumor suppressor miRNA, targeting overexpress oncogenes, leads to tumor suppressions.…”

“…High-mobility group AT-hook1 (HMGA1, formerly HMG-I/Y), an architectural transcription factor, participates in a number of tumor biological processes. Fu et al [68] have shown that HMGA1 is highly expressed in CSCC tissue, which promotes the migration and invasion of cervical cancer cells and showed that the mechanism of HMGA1 cancer promotion is targeting the promoter region of miR-221/222 to enhance the expression of miR-221/222. Among them, miR-221/222 targeted on the 3′UTR of tissue inhibitor of metalloproteinases 3 (TIMP3), while TIMP3 downregulated and MMP2/MMP9 upregulated, and miR-221/222-TIMP3-MMP2/MMP9 axis participates in the migration and invasion process ( Figure 5).…”