DDX3X loss is an adverse prognostic marker in diffuse large B-cell lymphoma and is associated with chemoresistance in aggressive non-Hodgkin lymphoma subtypes

Kizhakeyil, Atish; Zaini, Nurmahirah Binte Mohammed; Poh, Zhi Sheng; Wong, Brandon Han Siang; Loh, Xinpeng; Ng, Aik Seng; Low, Zun Siong; Prasannan, Praseetha; Gong, Chun; Tan, Meiling; Nagarajan, Chandramouli; Huang, Dachuan; Lu, Pang Wan; Lim, Jing Quan; Barrans, Sharon; Ong, Choon Kiat; Lim, Soon Thye; Chng, Wee Joo; Follows, George; Hodson, Daniel J.; Du, Ming; Goh, Yeow Tee; Tan, Suat Hoon; Grigoropoulos, Nicholas F.; Verma, Navin Kumar

doi:10.1186/s12943-021-01437-0

Cited by 10 publications

(11 citation statements)

References 15 publications

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“…The cell cycle is a well-defined series of steps that a cell follows as it grows (G1), duplicates its DNA (S phase), gets ready to divide (G2), and divides (M phase) . In our study, UA was shown to arrest the cell cycle of CRC at the G0/G1 phase, with a reduced proportion in the S phase and lowered expression of cyclin D1, which potentiated resultant CRC apoptosis . Consistently, it is documented that UA causes apoptosis and anoikis and blocks the cell cycle at the G1/G0 phase of RKO cells, with less cell cycle distribution at the S phase …”

Section: Discussionsupporting

confidence: 85%

“…41 In our study, UA was shown to arrest the cell cycle of CRC at the G0/G1 phase, with a reduced proportion in the S phase and lowered expression of cyclin D1, which potentiated resultant CRC apoptosis. 42 Consistently, it is documented that UA causes apoptosis and anoikis and blocks the cell cycle at the G1/G0 phase of RKO cells, with less cell cycle distribution at the S phase. 21 The Wnt signaling pathway begins with the binding of the Wnt protein ligand to the cell membrane Frizzled family receptor, transducing the signal to Dvl (disheveled) protein within the cell.…”

Section: Discussionmentioning

confidence: 67%

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Ursolic Acid Suppresses Colorectal Cancer by Down-Regulation of Wnt/β-Catenin Signaling Pathway Activity

Zhao

Tang

Qiu

et al. 2023

J. Agric. Food Chem.

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Overwhelming evidence points to an abnormally active Wnt/β-catenin signaling as a key player in colorectal cancer (CRC) pathogenesis. Ursolic acid (UA) is a pentacyclic triterpenoid that has been found in a broad variety of fruits, spices, and medicinal plants. UA has been shown to have potent bioactivity against a variety of cancers, including CRC, with the action mechanism obscure. Our study tried to learn more about the efficacy of UA on CRC and its functional mechanism amid the Wnt/β-catenin signaling cascade. We determined the efficacy of UA on CRC SW620 cells with respect to the proliferation, migration, clonality, apoptosis, cell cycle, and Wnt/β-catenin signaling cascade, with assessment of the effect of UA on normal colonic NCM460 cells. Also, the effects of UA on the tumor development, apoptosis, cell cycle, and Wnt/β-catenin signaling axis were evaluated after a subcutaneous SW620 xenograft tumor model was established in mice. In this work, we showed that UA drastically suppressed proliferation, migration, and clonality; induced apoptosis; and arrested the cell cycle at the G0/G1 phase of SW620 cells, without the influence on NCM460 cells, accompanied by weakened activity of the Wnt/β-catenin signaling pathway. Besides, UA markedly deterred the growth of the xenograft tumor, ameliorated pathological features, triggered apoptosis, and arrested the cell cycle in xenograft CRC tissue, by lessening the Wnt/β-catenin signaling cascade. Overall, UA may inhibit the malignant phenotype, induce apoptosis, and arrest the cell cycle of CRC, potentially by attenuating the Wnt/β-catenin signaling axis, providing insights into the mechanism for the potency of UA on CRC.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 67%

Ursolic Acid Suppresses Colorectal Cancer by Down-Regulation of Wnt/β-Catenin Signaling Pathway Activity

Zhao

Tang

Qiu

et al. 2023

J. Agric. Food Chem.

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“…Kizhakeyil et al established the DDX3X ‐mutant and DDX3X ‐knockout cell lines to observe their effects on the proliferation, apoptosis, and other phenotypes of the cell lines. The results showed that the overexpression of wild‐type DDX3X in the U2932 and HuT78 cells significantly decreased their proliferation 23 . Lacroix et al revealed that DDX3X was required for the lymphoid differentiation and MYC‐driven lymphomagenesis, which indicated that inhibiting the expression of the DDX3X gene could be a treatment strategy for the MYC‐driven B‐cell lymphoma 25 .…”

Section: Discussionmentioning

confidence: 99%

Characteristics and prognosis of rrDLBCL with TP53 mutations and a high‐risk subgroup represented by the co‐mutations of DDX3X‐TP53

Gao

Hu²,

Zheng³

et al. 2023

Cancer Medicine

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Background TP53 mutations have a prognostic significance in relapsed and refractory diffuse large B‐cell lymphoma (rrDLBCL) patients, and their treatment still faces a great challenge. This study aimed to evaluate the prognosis of patients with TP53 mutations (TP53mut) in the context of CAR‐T therapy (Chimeric antigen receptor T‐cell therapy) as well as explore the heterogeneity in their cohort and identify the possible risk factors. Methods A retrospective study was conducted to investigate the clinical characteristics of rrDLBCL patients with TP53 mutations and their prognostic factors, receiving CAR‐T therapy. And the expression level of TP53 and DDX3X, which was an important co‐mutation of TP53 revealed in the cohort, were explored in public databases and cell lines. Results The median overall survival time of 40 patients with TP53 mutations was 24.5 months, while their median progression‐free survival time after CAR‐T was 6.8 months. There were no significant differences in the ORR (objective remission rate, X2 = 3.0498, p > 0.05) and PFS (after CAR‐T therapy) between the patients with wild‐type and mutated TP53 genes after CAR‐T therapy, while the OS of patients with TP53 mutations was significantly worse (p < 0.01). In patients with TP53 mutations, the performance status (ECOG score) was identified as the most important prognostic factor, while the efficacies of induction and salvage treatments were also correlated with the prognosis. Among molecular indicators, the co‐mutations of Chr‐17 and those located on the exon 5 of the TP53 gene showed a tendency for a worse prognosis. Moreover, the patients with TP53‐DDX3X co‐mutations were identified as a subgroup with an extremely bad prognosis. The expression levels of DDX3X and TP53 were explored in a public database and the cell lines with their co‐mutations, which indicated that inhibiting the DDX3X gene could affect the proliferation of rrDLBCL cells and the expression of TP53. Conclusions This study indicated rrDLBCL patients with TP53 mutations was still the group of poor prognosis in the CAR‐T therapy era. CAR‐T therapy can benefit some TP53mut patients, and the performance status (ECOG) might help predict their prognosis. The study also revealed a subgroup of TP53‐DDX3X co‐mutations in rrDLBCL, which showed a strong clinical significance.

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“…This loss of function of DDX3X abnormally activates NF-κB and MAPK pathways at the transcriptional level and is associated with an impaired ability to suppress cell cycle progression [ 52 ]. DDX3X mutated proteins are also connected to an increase in STAT3/p42/p44 phosphorylation and to the development of chemoresistance [ 53 ]. Finally, high levels of DDX3X expression in gastric cancer are correlated with a better prognosis and patient survival [ 42 ].…”

Section: The Ddx3x Rna Helicasementioning

confidence: 99%

DEAD-Box RNA Helicases DDX3X and DDX5 as Oncogenes or Oncosuppressors: A Network Perspective

Secchi

Lodola

Garbelli

et al. 2022

Cancers

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RNA helicases of the DEAD-box family are involved in several metabolic pathways, from transcription and translation to cell proliferation, innate immunity and stress response. Given their multiple roles, it is not surprising that their deregulation or mutation is linked to different pathological conditions, including cancer. However, while in some cases the loss of function of a given DEAD-box helicase promotes tumor transformation, indicating an oncosuppressive role, in other contexts the overexpression of the same enzyme favors cancer progression, thus acting as a typical oncogene. The roles of two well-characterized members of this family, DDX3X and DDX5, as both oncogenes and oncosuppressors have been documented in several cancer types. Understanding the interplay of the different cellular contexts, as defined by the molecular interaction networks of DDX3X and DDX5 in different tumors, with the cancer-specific roles played by these proteins could help to explain their apparently conflicting roles as cancer drivers or suppressors.

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DDX3X loss is an adverse prognostic marker in diffuse large B-cell lymphoma and is associated with chemoresistance in aggressive non-Hodgkin lymphoma subtypes

Cited by 10 publications

References 15 publications

Ursolic Acid Suppresses Colorectal Cancer by Down-Regulation of Wnt/β-Catenin Signaling Pathway Activity

Ursolic Acid Suppresses Colorectal Cancer by Down-Regulation of Wnt/β-Catenin Signaling Pathway Activity

Characteristics and prognosis of rrDLBCL with TP53 mutations and a high‐risk subgroup represented by the co‐mutations of DDX3X‐TP53

DEAD-Box RNA Helicases DDX3X and DDX5 as Oncogenes or Oncosuppressors: A Network Perspective

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