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Molecular genetics of lung cancer
Published in J. K. Cowell, Molecular Genetics of Cancer, 2003
Frederic J. Kaye, Akihito Kubo
The recognition that the viral transforming proteins from adenovirus, simian virus 40 (SV40), and human papillomavirus (HPV) could precipitate the RB1 product led to a model where RB tumor suppressor function is mediated through a ‘pocket’ protein-binding activity (Weinberg, 1995). In addition to RB1, however, several other protein species are co-precipitated by the same viral transforming proteins (Whyte et al., 1989). Two of these unknown species were initially designated as pl07 and pl30 according to their apparent molecular weights on SDS-PAGE gels. The subsequent isolation of these genes revealed that they were highly related to RB1, especially in the central domains that are responsible for generating the ‘pocket’ protein binding function (Ewen et al., 1991; Li et al., 1993; Mayol et al., 1993). The roles of the RB-related 1 gene (RBL1/pl07) and the RB-related 2 gene (RBL2/pl30), however, are still undefined (Kaye, 1998). Ectopic expression of all three RB1-related gene members results in growth suppression of mammalian cells and it has been suggested that inactivation of RBL1 and RBL2 may be required in vitro to manifest the fully transformed phenotype even in RB1−/− cells. In contrast to the RB1 gene, however, mutational inactivation of these RB1-related genes has not, until recently, been observed in human tumor samples. In 1997, investigators reported that 1/19 SCLC cell lines showed inactivation of the RBL2/p130 gene (Helin et al., 1997). Subsequently other investigators reported that approximately 30% of non-SCLC had altered expression of RBL2 by immunohistochemistry which was associated with a worse clinical outcome (Baldi et al., 1997). In addition, these authors have reported an unusual clustering of mutations in a wide range of human tumors predominantly within the carboxy-terminal exons of RBL2 (Cinti et al., 2000; Claudio et al., 2000a). For example, they reported that 11/14 lung cancer samples showed multiple missense and frameshift RBL2 mutations (Claudio et al., 2000b). In contrast, however, we have not identified mutational inactivation in either the RBL1/p107 or the RBL2/p130 gene in a large collection of SCLC and non-SCLC tumor cell lines (Modi et al., 2000). Therefore, while simultaneous inactivation of multiple RB-related family members in lung cancer is an important hypothesis, the role of RBL1 and RBL2 is still undefined.
Novel chromobox 2 inhibitory peptide decreases tumor progression
Published in Expert Opinion on Therapeutic Targets, 2023
Lindsay W. Brubaker, Donald S. Backos, Vu T. Nguyen, Philip Reigan, Tomomi M Yamamoto, Elizabeth R. Woodruff, Ritsuko Iwanaga, Michael F. Wempe, Vijay Kumar, Christianne Persenaire, Zachary L. Watson, Benjamin G. Bitler
Importantly, ovarian cancer is not the only potential cancer for utilization of CBX2 as a possible therapeutic target as CBX2 drives tumor progression of multiple cell types, including prostate, breast, glioma, and gastric cancers [37–42]. In prostate cancer, Clermont et al. found that CBX2 was recurrently upregulated in metastatic prostate cancer and that elevated CBX2 expression was correlated with poor clinical outcomes [41]. Furthermore, CBX2 depletion abrogated cell viability and induced apoptosis in metastatic prostate cancer cell lines, suggesting that CBX2 controls the expression of key regulators of cell proliferation and metastasis, again raising the questions of potential utility of CBX2 as a therapeutic target [41]. In breast cancer, literature suggests that CBX2 is overexpressed and plays a critical role in tumor progression [43]. In vitro data suggests that increased expression CBX2 may lead to activation of the PI3K/AKT pathway [43] and that CBX2 may ultimately inhibit RBL2 activity leading to inhibition of a protein complex that limits cell growth, thereby driving tumor progression [22]. These authors raise the question of CBX2 as a potential therapeutic target in breast cancer.
Genomic complexity is associated with epigenetic regulator mutations and poor prognosis in diffuse large B-cell lymphoma
Published in OncoImmunology, 2021
Hua You, Zijun Y. Xu-Monette, Li Wei, Harry Nunns, Máté L. Nagy, Govind Bhagat, Xiaosheng Fang, Feng Zhu, Carlo Visco, Alexandar Tzankov, Karen Dybkaer, April Chiu, Wayne Tam, Youli Zu, Eric D. Hsi, Fredrick B. Hagemeister, Jooryung Huh, Maurilio Ponzoni, Andrés J.M. Ferreri, Michael B. Møller, Benjamin M. Parsons, J. Han Van Krieken, Miguel A. Piris, Jane N. Winter, Yong Li, Qingyan Au, Bing Xu, Maher Albitar, Ken H. Young
To gain further biological insight, we compared the gene expression profiles of MUThigh and MUTlow patients. Prominent GEP signatures were identified for MUThigh in overall cohort, the WT-TP53 subset, and the WT-TP53 GCB subset (Figure 4(a)). Notable signatures among the large number of upregulated genes in MUThigh WT-TP53 GCB included IGHM, voltage-gated ion channel components/regulators (CLCN1, CLCN2, KCNH4, KCNA4, CABP2), p53 inhibitor AGR2, and paradoxically several tumor suppressors and positive regulators of the p53 pathway (DHRS2 that attenuates MDM2-mediated p53 degradation, pro-apoptotic BBC3, SIK1 with role in p53-dependent anoikis and metastasis suppression, CADM4, and INSM2). Downregulated genes included those functioning in tumor suppression (CCDC6, RBL2, NEMF, BCLAF1, RASA1), mRNA metabolism and/or translation regulation (STAU1, SP3, DDX6, PABPC3), cell cycle (NSA2, ANAPC16, PCNP), epigenetic regulation (SMARCA5), degradation (UBE2D2, FEM1C), and others (Table 3.). Among DNA repair genes, HDAC1, ITM2A, PARP1, BCL11B, GATAD2B, and RAB27A were downregulated whereas PARP3, XRCC3, RAD54L, and ERCC2 were upregulated in MUThigh cases. The GO class and gene categories for differentially expressed genes are listed in Table 3. As the MUThigh gene signatures showed involvement of the p53 pathway, we compared the p53/MDM2 expression26,28 in MUThigh and MUTlow patients with WT-TP53. Only in ABC-DLBCL with WT-TP53, MUThigh patients was significantly associated with higher mean levels of WT-p53 and MDM2 overexpression (Figure 4(b)).
The Roles of MicroRNA in Pancreatic Cancer Progression
Published in Cancer Investigation, 2022
Ramya Devi KT, Dharshene Karthick, Kirtikesav Salem Saravanaraj, M. K. Jaganathan, Suvankar Ghorai, Sanjana Prakash Hemdev
The miR-21 negatively regulates the expression of the FoxO1 (Forkhead box O1) transcription factor, and hence its overexpression deregulates the cell cycle checkpoints along with the promotion of cancerous growth (20). Also, it has been reported to downregulate the expression of tumour suppressor genes, PDCD4 (programmed cell death 4), and TIMP3 (tissue inhibitor metallopeptidase 3) in the case of PDAC (21). Huang et al. found that miR-233 shows increased expression and is associated with Cisplatin (CDDP) resistance in pancreatic cancer cells. Inhibition of miR-223 expression has upregulated FoxO3a (Forehead box O3a) expression, restrained pancreatic cancer cell proliferation, promoted cell apoptosis, and enhanced CDDP sensitivity in pancreatic cancer cells (22). miR-371, miR-182-5p, and miR-10b are overexpressed also in patients of PDAC, leading to an increase in the proliferation levels of tumour cells. Further, miR-182-5p causes the arrest of tumour cells in the S phase of the cell division cycle while miR-10b increases the invasive power of tumour cells in pancreatic cancer. The induction of apoptosis and promotion of cell cycle arrest is taking place with a lower level expression of miR-130b by transducer and activator of transcription in PDAC (23). The expression of miR-205 and miR-200 is induced by KRAS, which is highly mutated in PDAC and resulted in the accumulation of reactive oxygen species which may mediate cell proliferation in pancreatic cancer (24). Overexpression of miR-221, p-JAK, and p-STAT3 increases the proliferation potency of PANC-1 cells (25). Additionally, the downregulation of miR-876-3p in PDAC tissues inhibits cell growth and the metastatic phenotype, implying that it is overexpressed in pancreatic cancer patients (26). miR-17-5P enhances pancreatic cancer cell proliferation by targeting RBL2 (Retinoblastoma- like protein 2) via disruption of the RBL2/E2F4-associated gene-repressing complexes in PDAC (27).