Departamento de Bioquímica, CINVESTAV-IPN, Ciudad de México, México.
Laboratorio de Medicina Traslacional y Departamento de Tumores Gastrointestinales, Instituto Nacional de Cancerología, Ciudad de México, México.
Curr Pharm Biotechnol. 2022;23(2):221-234. doi: 10.2174/1389201022666210224130022.
Endometrial cancer represents the most frequent neoplasia from the corpus uteri and comprises the 14th leading cause of death in women worldwide. Risk factors that contribute to the disease include early menarche, late menopause, nulliparity, and menopausal hormone use, as well as hypertension and obesity comorbidities. The clinical effectiveness of chemotherapy is variable, suggesting that novel molecular targeted therapies against specific cellular processes associated with the maintenance of cancer cell survival and therapy resistance ameliorate the rates of success in endometrial cancer treatment. In the course of tumor growth, cancer cells must adapt to decreased oxygen availability in the microenvironment by upregulation of hypoxia-inducible factors, which orchestrate the activation of a transcriptional program leading to cell survival. During this adaptative process, the hypoxic cancer cells may acquire invasive and metastatic properties as well as increased cell proliferation and resistance to chemotherapy, enhanced angiogenesis, vasculogenic mimicry, and maintenance of cancer cell stemness, which contribute to more aggressive cancer phenotypes. Several studies have shown that hypoxia-inducible factor 1 alpha (HIF-1α) protein is aberrantly overexpressed in many solid tumors of the breast, prostate, ovarian, bladder, colon, brain, and pancreas. Thus, it has been considered an important therapeutic target. Here, we reviewed the current knowledge of the relevant roles of cellular hypoxia mechanisms and HIF-1α functions in diverse processes associated with endometrial cancer progression. In addition, we also summarize the role of microRNAs in the posttranscriptional regulation of protein-encoding genes involved in the hypoxia response in endometrial cancer. Finally, we pointed out the need for urgent targeted therapies to impair the cellular processes activated by hypoxia in the tumor microenvironment.
子宫内膜癌是最常见的子宫体肿瘤，也是全球女性第 14 大死亡原因。导致这种疾病的危险因素包括初潮早、绝经晚、不孕、绝经后激素使用、高血压和肥胖合并症。化疗的临床效果是可变的，这表明针对与维持癌细胞存活和治疗耐药性相关的特定细胞过程的新型分子靶向治疗可以提高子宫内膜癌治疗的成功率。在肿瘤生长过程中，癌细胞必须通过上调缺氧诱导因子来适应微环境中氧可用性的降低，这些因子协调激活导致细胞存活的转录程序。在这个适应过程中，缺氧的癌细胞可能获得侵袭性和转移性特性，以及增加的细胞增殖和对化疗的耐药性、增强的血管生成、血管生成拟态和维持癌细胞干性，这有助于更具侵袭性的癌症表型。多项研究表明，缺氧诱导因子 1α（HIF-1α）蛋白在乳腺癌、前列腺癌、卵巢癌、膀胱癌、结肠癌、脑癌和胰腺癌等多种实体肿瘤中异常过表达。因此，它被认为是一个重要的治疗靶点。在这里，我们综述了细胞缺氧机制和 HIF-1α 功能在与子宫内膜癌进展相关的多种过程中的相关作用。此外，我们还总结了 microRNAs 在子宫内膜癌中缺氧反应相关蛋白编码基因的转录后调控中的作用。最后，我们指出需要紧急靶向治疗来削弱肿瘤微环境中缺氧激活的细胞过程。
