The reciprocal interplay between TNFα and the circadian clock impacts on cell proliferation and migration in Hodgkin lymphoma cells

Abstract

A bidirectional interaction between the circadian network and effector mechanisms of immunity brings on a proper working of both systems. In the present study, we used Hodgkin lymphoma (HL) as an experimental model for a type of cancer involving cells of the immune system. We identified this cancer type among haematological malignancies has having a strong differential expression of core-clock elements. Taking advantage of bioinformatics analyses and experimental procedures carried out in III- and IV-stage HL cells, and lymphoblastoid B cells, we explored this interplay and bear out diverse interacting partners of both systems. In particular, we assembled a wide-ranging network of clock-immune-related genes and pinpointed TNF as a crucial intermediary player. A robust circadian clock hallmarked III-stage lymphoma cells, differently from IV-stage HL cells, which do not harbour a properly functioning clockwork. TNF and circadian gene modulation impacted on clock genes expression and triggered phenotypic changes in lymphoma cells, suggesting a crucial involvement of core-clock elements and TNF in the physiopathological mechanisms hastening malignancy. Our results move forward our understanding of the putative role of the core-clock and TNF in the pathobiology of Hodgkin lymphoma, and highlight their influence in cellular proliferation and migration in lymphatic cancers.

The Cancer Clock Is (Not) Ticking: Links between Circadian Rhythms and Cancer

“…In chronic lymphocytic leukemia, the ratio of PER2 to CRY1 is suggested to be a prognostic marker that predicts survival outcomes of patients, with a low PER2:CRY1 having the best outcomes [88]. Furthermore, increased TNF in Hodgkin lymphoma cells has been found to alter core-clock gene expression and cell cycle phase, impacting cell proliferation and migration [89].…”

An Optimal Time for Treatment—Predicting Circadian Time by Machine Learning and Mathematical Modelling

“…Given the range of molecular time-dependent processes that the circadian clock regulates, including metabolism, DNA repair and the cell cycle, it has the potential to act as a tumor suppressor [ 25 , 46 ]. Indeed, several clock-controlled genes show a strong association with cancer and cancer progression, in particular genes related to metabolism [ 26 , 28 , 44 ]. In reverse, cancer also impacts the core-clock network [ 48 ], which, when implemented into a combined model, will result in a complex interaction between the core-clock and the cancer network.…”

“…The interplay between these two transcription/translation feedback loops orchestrates the circadian oscillatory mechanism in cells ( Figure 1 A). This intricate time keeping system plays a significant role in regulating various molecular and cellular functions from RNA processing to immune pathways, it controls several steps in metabolic pathways and governs the expression patterns of numerous cell cycle proteins [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. Subsequently, disruption in circadian processes may not only favor cancer progression but also result in various other pathologies [ 33 , 34 , 35 , 36 ].…”

The tumour suppressing role of the circadian clock

“…On the contrary, the immune system is able to regulate the circadian clock. A comprehensive bidirectional communication between the two systems has recently been described . The link between the two processes is evidenced by the bidirectional regulation of clock proteins and cytokines, and TNFα has been found to be the major bridging element between the two systems in Hodgkin lymphoma cells .…”

“…A comprehensive bidirectional communication between the two systems has recently been described . The link between the two processes is evidenced by the bidirectional regulation of clock proteins and cytokines, and TNFα has been found to be the major bridging element between the two systems in Hodgkin lymphoma cells . Clock proteins have been shown to temporally regulate cytokine expression , for example, secretion of proinflammatory cytokines, TNFα and IL6, displays circadian oscillation in macrophages .…”