TCF4 promotes colorectal cancer drug resistance and stemness via regulating ZEB1/ZEB2 expression

The present study aims to investigate the roles of TCF4 and its underlying mechanism in colorectal cancer (CRC). Doxorubicin-resistant DLD-1 (DLD1 DR), TCF4 overexpression, and TCF4 knockdown cell lines were constructed. A flow cytometer was used to analyze frequencies of CD133+ cell in the DLD1 and DLD1 DR cells. Quantitative real-time PCR (qPCR) was used to determine the expressions of cancer stem cell (CSC) makers. Stemness of CRC cells were determined using tumorsphere formation assay. The correlation between TCF4 and ZEB1/ZEB2 were determined using public data from The Cancer Genome Atlas (TCGA) datasets. ZEB1/ZEB2 overexpression cell lines were constructed and cell viabilities were then determined using MTT and colony formation assays. TCF4 overexpression promoted proliferation of CRC cell lines and relative expressions of TCF4 were significantly increased in the DLD1 DR cells. TCF4 overexpression promoted CRC cell doxorubicin resistance, whereas TCF4 knockdown significantly decreased doxorubicin resistance. Additionally, TCF4 overexpression also significantly increased frequencies of CSC cells, expressions of CSC markers, and CRC ability to form tumorsphere. Furthermore, TCF4 promoted ZEB1 and ZEB2 expression, leading to CRC proliferation and doxorubicin resistance. TCF4 promoted CRC doxorubicin resistance and stemness by regulating expressions of ZEB1 and ZEB2.     

CHFR regulates chemoresistance in triple-negative breast cancer through destabilizing ZEB1

Failures to treat triple-negative breast cancer (TNBC) are mainly due to chemoresistance or radioresistance. We and others previously discovered that zinc finger E-box-binding homeobox 1 (ZEB1) is a massive driver causing these resistance. However, how to dynamically modulate the intrinsic expression of ZEB1 during cell cycle progression is elusive. Here integrated affinity purification combined with mass spectrometry and TCGA analysis identify a cell cycle-related E3 ubiquitin ligase, checkpoint with forkhead and ring finger domains (CHFR), as a key negative regulator of ZEB1 in TNBC. Functional studies reveal that CHFR associates with and decreases ZEB1 expression in a ubiquitinating-dependent manner and that CHFR represses fatty acid synthase (FASN) expression through ZEB1, leading to significant cell death of TNBC under chemotherapy. Intriguingly, a small-molecule inhibitor of HDAC under clinical trial, Trichostatin A (TSA), increases the expression of CHFR independent of histone acetylation, thereby destabilizes ZEB1 and sensitizes the resistant TNBC cells to conventional chemotherapy. In patients with basal-like breast cancers, CHFR levels significantly correlates with survival. These findings suggest the therapeutic potential for targeting CHFR-ZEB1 signaling in resistant malignant breast cancers.Subject terms: Cancer therapy, Cell death, Post-translational modifications     

双特异性抗体在肿瘤治疗中的研究

双特异性抗体(bispecific antibody,BsAb)有两个抗原结合位点,其中一个位点可与靶细胞表面抗原结合,另一个位点则可与载荷物(如效应细胞,分子等)结合。将BsAb应用于肿瘤治疗,发挥抗肿瘤效应的思想已有二十多年历史,随着对效应细胞生物学了解的加深和抗体工程的飞速发展,各种形式的BsAb相继出现,多种BsAb药物已进入临床初期试验或治疗使用阶段。本文就BsAb的各种新形式及其在肿瘤治疗中的应用新进展作简要概述。     

宫颈癌患者人乳头瘤病毒感染情况及STING、ZEB1蛋白水平分析

分析宫颈癌患者人乳头瘤病毒（HPV）感染情况及癌灶组织内干扰素基因刺激因子（STING）、E盒锌指结合蛋白1（ZEB1）表达情况,为该类患者的治疗提供参考。

收集我院病理检验科2019年1月至2022年1月63例宫颈癌标本（宫颈癌组）、55例宫颈上皮内瘤变（CIN）标本（CIN组）及50例正常宫颈标本（正常组）,采用免疫组化法检测各标本内STING及ZEB1表达情况,采用原位杂交法检测各标本内高危HPV感染情况,分析STING及ZEB1蛋白表达情况与宫颈癌病理特征及高危HPV感染之间的关系。

宫颈癌组标本STING及ZEB1表达量均高于CIN组及正常组,CIN组标本ZEB1表达量高于正常组,差异均有统计学意义（均P＜0.05）;CIN组标本STING表达量与正常组比较差异无统计学意义（P＞0.05）。宫颈癌组标本HPV16、18检出率高于CIN组及正常组,CIN组标本HPV16、18检出率高于正常组,差异均有统计学意义（均P＜0.05）。宫颈癌患者FIGO分期及浸润深度与其组织内STING及ZEB1蛋白阳性情况均存在相关性;此外,宫颈癌淋巴结转移及肿瘤分化程度与组织内STING蛋白阳性情况存在相关性,差异均有统计学意义（均P＜0.05）。宫颈癌患者STING及ZEB1蛋白表达与其HPV16、18检出率间均呈正相关（均P＜0.05）。

宫颈癌组标本STING及ZEB1蛋白表达量均高于正常组及CIN组,且其表达量还与宫颈癌浸润、FIGO分期相关。STING和ZEB1可能与HPV16、18感染共同参与宫颈癌的发生及进展。

     

The ZEB1/miR-200 feedback loop controls Notch signalling in cancer cells

Notch signalling is important for development and tissue homeostasis and activated in many human cancers. Nevertheless, mutations in Notch pathway components are rare in solid tumours. ZEB1 is an activator of an epithelial-mesenchymal transition (EMT) and has crucial roles in tumour progression towards metastasis. ZEB1 and miR-200 family members repress expression of each other in a reciprocal feedback loop. Since miR-200 members target stem cell factors, ZEB1 indirectly induces stemness maintenance and associated drug resistance. Here, we link ZEB1 and its cancer promoting properties to Notch activation. We show that miR-200 members target Notch pathway components, such as Jagged1 (Jag1) and the mastermind-like coactivators Maml2 and Maml3, thereby mediating enhanced Notch activation by ZEB1. We further detected a coordinated upregulation of Jag1 and ZEB1, associated with reduced miR-200 expression in two aggressive types of human cancer, pancreatic adenocarcinoma and basal type of breast cancer. These findings explain increased Notch signalling in some types of cancers, where mutations in Notch pathway genes are rare. Moreover, they indicate an additional way how ZEB1 exerts its tumour progressing functions.     

Recent advances in breast cancer metastasis suppressor 1

Metastasis is a complex process divided into a number of steps including detachment of tumor cells from the primary tumor, invasion, migration, intravasation, survival in the vasculature, extravasation, and colonization of the secondary site. Proteins that block metastasis without inhibiting primary tumor formation are known as metastasis suppressors; examples are NM23, Maspin, KAI1, KISS1, and MKK4. Breast cancer metastasis suppressor 1 (BRMS1) was identified as a suppressor of breast cancer metastasis in the late 1990s. In vitro and in vivo studies have confirmed that BRMS1 is a potent metastasis suppressor not limited to breast cancer. However, conflicting clinical observations regarding its role as a metastasis suppressor and its validity as a diagnostic biomarker warrant more in-depth clinical study. In this review, the authors provide an overview of its biology, function, action mechanism and pathological significance.     

Recent advances in PTP1B signaling in metabolism and cancer

Protein tyrosine phosphorylation is one of the major post-translational modifications in eukaryotic cells and represents a critical regulatory mechanism of a wide variety of signaling pathways. Aberrant protein tyrosine phosphorylation has been linked to various diseases, including metabolic disorders and cancer. Few years ago, protein tyrosine phosphatases (PTPs) were considered as tumor suppressors, able to block the signals emanating from receptor tyrosine kinases. However, recent evidence demonstrates that misregulation of PTPs activity plays a critical role in cancer development and progression. Here, we will focus on PTP1B, an enzyme that has been linked to the development of type 2 diabetes and obesity through the regulation of insulin and leptin signaling, and with a promoting role in the development of different types of cancer through the activation of several pro-survival signaling pathways. In this review, we discuss the molecular aspects that support the crucial role of PTP1B in different cellular processes underlying diabetes, obesity and cancer progression, and its visualization as a promising therapeutic target.