Deregulation of LIMD1–VHL–HIF-1α–VEGF pathway is associated with different stages of cervical cancer

Abstract

To understand the mechanism of cellular stress in basal-parabasal layers of normal cervical epithelium and during different stages of cervical carcinoma, we analyzed the alterations (expression/methylation/copy number variation/mutation) of HIF-1α and its associated genes LIMD1, VHL and VEGF in disease-free normal cervix ( = 9), adjacent normal cervix of tumors ( = 70), cervical intraepithelial neoplasia (CIN; = 32), cancer of uterine cervix (CACX; = 174) samples and two CACX cell lines. In basal-parabasal layers of normal cervical epithelium, LIMD1 showed high protein expression, while low protein expression of VHL was concordant with high expression of HIF-1α and VEGF irrespective of HPV-16 (human papillomavirus 16) infection. This was in concordance with the low promoter methylation of LIMD1 and high in VHL in the basal-parabasal layers of normal cervix. LIMD1 expression was significantly reduced while VHL expression was unchanged during different stages of cervical carcinoma. This was in concordance with their frequent methylation during different stages of this tumor. In different stages of cervical carcinoma, the expression pattern of HIF-1α and VEGF was high as seen in basal-parabasal layers and inversely correlated with the expression of LIMD1 and VHL. This was validated by demethylation experiments using 5-aza-2'-deoxycytidine in CACX cell lines. Additional deletion of LIMD1 and VHL in CIN/CACX provided an additional growth advantage during cervical carcinogenesis through reduced expression of genes and associated with poor prognosis of patients. Our data showed that overexpression of HIF-1α and its target gene VEGF in the basal-parabasal layers of normal cervix was due to frequent inactivation of VHL by its promoter methylation. This profile was maintained during different stages of cervical carcinoma with additional methylation/deletion of VHL and LIMD1.

LIMD1‐AS1 suppressed non‐small cell lung cancer progression through stabilizing LIMD1 mRNA via hnRNP U

“…Previous studies have suggested that LIMD1 participates in tumor progression of diverse cancers by serving as a tumor‐suppressor, such as in gastric cancer and cervical cancer . Also, LIMD1 is revealed by former studies to present low expression and hinder tumor growth In NSCLC .…”

“…A number of studies reveal that deletion of LIMD1 results in aberrant cellular behaviors, such as cell cycle perturbation and hyperproliferation of cells . The tumor‐suppressive impact of LIMD1 is supported by studies in multiple cancers, such as gastric cancer and cervical cancer . In NSCLC, evidence proves that LIMD1 is downregulated and results in the misregulation of retinoblastoma protein (pRB) and cell cycle .…”

STAT3 expression is correlated with pathological stage in luminal subtypes of breast carcinoma

“…HIFs mainly increase the angiogenesis, and cause the progression of the tumor in an aggressive course (46,48). The literature has revealed a signifi cant association between low surveillance and high HIF1α levels in patients with bladder, breast, endometrial, cervical, oropharyngeal and esophageal carcinomas (45,(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61). In addition, HIF1α has been reported to be associated with poor prognosis in pancreatic tumors (62).…”

miR-550a-5p Functions as a Tumor Promoter by Targeting LIMD1 in Lung Adenocarcinoma

“…LIMD1 is a member of the Zyxin proteins, encoded at chromosome 3p21.3 and widely expressed in human tissues (22,23). A large number of previous studies have suggested that LIMD1 functions as a tumor suppressor (24)(25)(26)(27). In terms of molecular mechanism, LIMD1 could participate in cellular processes and pathways through its scaffold function, meaning that the tumorsuppressive function of LIMD1 is likely to be regulated by different signal cascades (28).…”