The Tumor Suppressive Role of PATZ1 in Thyroid Cancer: A Matter of Epithelial-Mesenchymal Transition

Abstract

PATZ1 is a chromatin-regulating factor with emerging roles in stemness and cancer. It has been suggested to play a dual oncogene/tumor suppressor role depending on the cellular context, but its function in human tumor biology is still far to be completely elucidated. We have recently identified its tumor suppressive role in thyroid carcinogenesis, possibly through the association between PATZ1 and p53 to oppose epithelial-mesenchymal transition and cell migration. These are major processes in tumor progression, local invasion, metastasis, and therapeutic resistance and play a recognized role in the development of thyroid cancer, particularly anaplastic thyroid carcinoma, but many questions about how they are orchestrated remain opened. Elucidation of the mechanisms regulating epithelial-mesenchymal transition and cell migration can suggest new candidates for antimetastatic drug development that could lead to more effective therapies for highly aggressive and lethal thyroid cancers.

Loss of One or Two PATZ1 Alleles Has a Critical Role in the Progression of Thyroid Carcinomas Induced by the RET/PTC1 Oncogene

“…Building on our previous results, showing that PATZ1 is downregulated in human thyroid carcinomas and plays a tumor suppressor role in thyroid cancer cells by inhibiting their malignant phenotype [ 10 , 22 ], we intercrossed RET/PTC1 TG [ 13 ] with Patz1-knockout mice [ 21 ] to better define the role of PATZ1 in thyroid carcinogenesis driven by the RET/PTC1 oncogene. As shown in Figure 1 a, double mutant RET/PTC1 TG ;Patz1 −/− mice developed thyroid tumors with higher incidence (100%) and earlier onset (median age of tumor incidence of 14 months) than their RET/PTC1 TG ;Patz1 +/+ compound mice (54% of tumors at a median age of 18 months) ( p = 0.0105, Log-rank (Mantell-Cox) test; HR = 0.3831; 95% CI 0.05877–0.6138).…”

“…It is worth noting that Patz1-knockout mice, previously characterized in a mixed c57BL/6J × 129SvJ genetic background [ 22 ], did not spontaneously develop thyroid carcinomas during their lifespan [ 10 ], while they do with the new mixed FVB/N × c57BL/6J × 129SvJ genetic background. Indeed, we showed here that RET/PTC1 WT ;Patz1 +/− mice develop thyroid carcinomas even with a minor incidence and a longer latency than RET/PTC1 TG ;Patz1 +/− mice.…”

“…Heterozygous Patz1-knockout mice [ 22 ] of a mixed 129SvJ × c57BL/6J strain were crossed to FVB/N mice expressing RET/PTC1 under the control of the bovine thyroglobulin promoter [ 14 ]. The resulting RET/PTC1 TG ;Patz1 +/− and RET/PTC1 wt ;Patz1 +/− mice were bred to generate six genotypic groups: RET/PTC1 TG ;Patz1 +/+ , RET/PTC1 TG ;Patz1 +/− , RET/PTC1 TG ;Patz1 −/− , RET/PTC1 wt ;Patz1 +/+ , RET/PTC1 wt ;Patz1 +/− , and RET/PTC1 wt ;Patz1 −/− .…”

Immunological Aspects of the Tumor Microenvironment and Epithelial-Mesenchymal Transition in Gastric Carcinogenesis

“…Physiologically, EMT can be observed during embryogenesis, tissue development and wound healing [48]. It is also a common phenomenon during carcinogenesis and can either induce or coexist with various malignancies such as breast cancer, thyroid cancer, cholangiocarcinoma, non-small cell lung carcinoma, colorectal cancer, inflammatory bowel disease or GC [49][50][51][52][53][54][55][56][57][58][59][60]. During the EMT process, ECs undergo a series of biochemical reactions that eventually lead to alterations in the cells' morphology, especially the loss of the polarity of cells [17,61].…”

The POZ/BTB and AT-Hook Containing Zinc Finger 1 (PATZ1) Transcription Regulator: Physiological Functions and Disease Involvement

“…The EMT is considered a critical process for the development of metastases and the acquisition of chemoresistance. In this context, blocking EMT might be a possible therapeutic approach and PATZ1 a valuable target to be activated [ 44 ]. In other human malignancies, such as Diffuse Large B Cell Lymphomas (DLBCL), the tumor suppressor function of PATZ1 is proapoptotic, achieved by inhibiting and enhancing transcription of BCL6 and BAX, respectively [ 41 ].…”