Ki67 is a Graded Rather than a Binary Marker of Proliferation versus Quiescence

Miller, Iain D.; Min, Mingwei; Yang, Chen; Tian, Chengzhe; Gookin, Sara E.; Carter, Dylan; Spencer, Steven J.

doi:10.1016/j.celrep.2018.06.110

Cited by 481 publications

(430 citation statements)

References 19 publications

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“…S13). Consistent with a recent publication (Miller et al, 2018), the Ki-67 staining of the nuclei was graded rather than binary (see Fig. S13, higher magnifications).…”

Section: P4ha1 Knockdown Affects the Architecture Of Wm239 Melanoma Tsupporting

confidence: 88%

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Prolyl 4‐hydroxylase subunit alpha 1 (P4HA1) is a biomarker of poor prognosis in primary melanomas, and its depletion inhibits melanoma cell invasion and disrupts tumor blood vessel walls

et al. 2020

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Melanoma is an unpredictable, highly metastatic malignancy, and treatment of advanced melanoma remains challenging. Novel molecular markers based on the alterations in gene expression and the molecular pathways activated or deactivated during melanoma progression are needed for predicting the course of the disease already in primary tumors and for providing new targets for therapy. Here, we sought to identify genes whose expression in primary melanomas correlate with patient disease‐specific survival using global gene expression profiling. Many of the identified potential markers of poor prognosis were associated with the epithelial–mesenchymal transition, extracellular matrix formation, and angiogenesis. We studied further the significance of one of the genes, prolyl 4‐hydroxylase subunit alpha 1 (P4HA1), in melanoma progression. P4HA1 depletion in melanoma cells reduced cell adhesion, invasion, and viability in vitro. In melanoma xenograft assays, we found that P4HA1 knockdown reduced melanoma tumor invasion as well as the deposition of collagens, particularly type IV collagen, in the interstitial extracellular matrix and in the basement membranes of tumor blood vessels, leading to vessel wall rupture and hemorrhages. Further, P4HA1 knockdown reduced the secretion of collagen triple helix repeat containing 1 (CTHRC1), an important mediator of melanoma cell migration and invasion, in vitro and its deposition around tumor blood vessels in vivo. Taken together, P4HA1 is an interesting potential prognostic marker and therapeutic target in primary melanomas, influencing many aspects of melanoma tumor progression.

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“…S13). Consistent with a recent publication (Miller et al, 2018), the Ki-67 staining of the nuclei was graded rather than binary (see Fig. S13, higher magnifications).…”

Section: P4ha1 Knockdown Affects the Architecture Of Wm239 Melanoma Tsupporting

confidence: 88%

“…, higher magnifications). The Ki‐67 labeling indices varied from 70% to 90% in different regions of both the control and P4HA1‐KD tumors, apparently depending on the growth rates and cell cycle phases of the heterogeneous tumor cells (Miller et al , ). The proliferation rates of the cells did not differ either in vitro .…”

Section: Resultsmentioning

confidence: 99%

Prolyl 4‐hydroxylase subunit alpha 1 (P4HA1) is a biomarker of poor prognosis in primary melanomas, and its depletion inhibits melanoma cell invasion and disrupts tumor blood vessel walls

et al. 2020

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“…Therefore TXA appears to promote the local immune response following TBI, by preventing plasmin‐mediated immunosuppression. Enhanced expression of Ki‐67 in CD11c+ cDC 1 week post TBI in TXA‐treated animals might represent longer‐lasting proliferation of this cell subset after TBI, based on a report demonstrating that this marker slowly degrades over time in the non‐proliferative phases of the cell cycle . This further supports the notion of enhanced proliferation of leukocytes in the cLN as one of the reasons for the increase in cellularity with TXA.…”

Section: Discussionmentioning

confidence: 55%

“…This response was unchanged by TXA ( Figure S4B). Since Ki-67 expression has been reported to be a dynamic process rather than to represent a binary parameter, 29 we also looked at the expression intensity of this marker within cells. CD11b+ cDC in the cLN of TXA-treated animals showed significantly enhanced expression of Ki-67 1 week post TBI compared to vehicle-treated mice F I G U R E 2 PAP complex formation and D-dimer levels were significantly elevated in the injured hemisphere 3 h post TBI, but this increase was inhibited by TXA.…”

Section: Tranexamic Acid Impacts On the Local Immune Response Follomentioning

confidence: 99%

Tranexamic acid modulates the cellular immune profile after traumatic brain injury in mice without hyperfibrinolysis

Draxler

Daglas

Fernando

et al. 2019

Journal of Thrombosis and Haemostasis

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Background Traumatic brain injury (TBI) is known to promote immunosuppression, making patients more susceptible to infection, yet potentially exerting protective effects by inhibiting central nervous system (CNS) reactivity. Plasmin, the effector protease of the fibrinolytic system, is now recognized for its involvement in modulating immune function. Objective To evaluate the effects of plasmin and tranexamic acid (TXA) on the immune response in wild‐type and plasminogen‐deficient (plg−/−) mice subjected to TBI. Methods Leukocyte subsets in lymph nodes and the brain in mice post TBI were evaluated by flow cytometry and in blood with a hemocytometer. Immune responsiveness to CNS antigens was determined by Enzyme‐linked Immunosorbent Spot (ELISpot) assay. Fibrinolysis was determined by thromboelastography and measuring D‐dimer and plasmin‐antiplasmin complex levels. Results Plg−/− mice, but not plg+/+ mice displayed increases in both the number and activation of various antigen‐presenting cells and T cells in the cLN 1 week post TBI. Wild‐type mice treated with TXA also displayed increased cellularity of the cLN 1 week post TBI together with increases in innate and adaptive immune cells. These changes occurred despite the absence of systemic hyperfibrinolysis or coagulopathy in this model of TBI. Importantly, neither plg deficiency nor TXA treatment enhanced the autoreactivity within the CNS. Conclusion In the absence of systemic hyperfibrinolysis, plasmin deficiency or blockade with TXA increases migration and proliferation of conventional dendritic cells (cDCs) and various antigen‐presenting cells and T cells in the draining cervical lymph node (cLN) post TBI. Tranexamic acid might also be clinically beneficial in modulating the inflammatory and immune response after TBI, but without promoting CNS autoreactivity.

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“…TIPE2 overexpression notably reduced the growth of rectal adenocarcinoma xenograft tumours, whereas TIPE2 knockdown markedly promoted tumour growth. Ki67, a nuclear nonhistone protein, is expressed by proliferating cells in all phases of the active cell cycle . The expression level of Ki67 is closely associated with the proliferation, invasiveness, and clinical outcome of a number of malignant tumours .…”

Section: Discussionmentioning

confidence: 99%

Tumour necrosis factor‐α‐induced protein 8‐like 2 is a novel regulator of proliferation, migration, and invasion in human rectal adenocarcinoma cells

Liu

Gao

et al. 2019

J Cellular Molecular Medi

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Tumour necrosis factor‐α‐induced protein 8‐like 2 (TIPE2) is a tumour suppressor in many types of cancer. However, the mechanism of action of TIPE2 on the growth of rectal adenocarcinoma is unknown. Our results showed that the expression levels of TIPE2 in human rectal adenocarcinoma tissues were higher than those in adjacent non‐tumour tissues. Overexpression of TIPE2 reduced the proliferation, migration, and invasion of human rectal adenocarcinoma cells and down‐regulation of TIPE2 showed reverse effects. TIPE2 overexpression increased apoptosis through down‐regulating the expression levels of Wnt3a, phospho (p)‐β‐Catenin, and p‐glycogen synthase kinase‐3β in rectal adenocarcinoma cells, however, TIPE2 knockdown exhibited reverse trends. TIPE2 overexpression decreased autophagy by reducing the expression levels of p‐Smad2, p‐Smad3, and transforming growth factor‐beta (TGF‐β) in rectal adenocarcinoma cells, however, TIPE2 knockdown showed opposite effects. Furthermore, TIPE2 overexpression reduced the growth of xenografted human rectal adenocarcinoma, whereas TIPE2 knockdown promoted the growth of rectal adenocarcinoma tumours by modulating angiogenesis. In conclusion, TIPE2 could regulate the proliferation, migration, and invasion of human rectal adenocarcinoma cells through Wnt/β‐Catenin and TGF‐β/Smad2/3 signalling pathways. TIPE2 is a potential therapeutic target for the treatment of rectal adenocarcinoma.

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Ki67 is a Graded Rather than a Binary Marker of Proliferation versus Quiescence

Cited by 481 publications

References 19 publications

Prolyl 4‐hydroxylase subunit alpha 1 (P4HA1) is a biomarker of poor prognosis in primary melanomas, and its depletion inhibits melanoma cell invasion and disrupts tumor blood vessel walls

Prolyl 4‐hydroxylase subunit alpha 1 (P4HA1) is a biomarker of poor prognosis in primary melanomas, and its depletion inhibits melanoma cell invasion and disrupts tumor blood vessel walls

Tranexamic acid modulates the cellular immune profile after traumatic brain injury in mice without hyperfibrinolysis

Tumour necrosis factor‐α‐induced protein 8‐like 2 is a novel regulator of proliferation, migration, and invasion in human rectal adenocarcinoma cells

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