Abstract
Programmed cell death 4 (PDCD4) is one multi-functional tumor suppressor inhibiting neoplastic transformation and tumor invasion. The role of PDCD4 in tumorigenesis has attracted more attention and has been systematically elucidated in cutaneous tumors. However, the normal biological function of PDCD4 in skin is still unclear. In this study, for the first time, we find that tumor suppressor PDCD4 is uniquely induced in a cell density-dependent manner in keratinocytes. To determine the potential role of PDCD4 in keratinocyte cell biology, we show that knockdown of PDCD4 by siRNAs can promote cell proliferation in lower cell density and partially impair contact inhibition in confluent HaCaT cells, indicating that PDCD4 serves as an important regulator of keratinocytes proliferation and contact inhibition in vitro. Further, knockdown of PDCD4 can induce upregulation of cyclin D1, one key regulator of the cell cycle. Furthermore, the expression patterns of PDCD4 in normal skin, different hair cycles and the process of wound healing are described in detail in vivo, which suggest a steady-state regulatory role of PDCD4 in epidermal homeostasis and wound healing. These findings provide a novel molecular mechanism for keratinocytes’ biology and indicate that PDCD4 plays a role in epidermal homeostasis.
Highlights
Programmed cell death 4 (PDCD4) is a tumor suppressor that has been implicated in the development of a broad spectrum of human tumors
For the first time, we found that tumor suppressor PDCD4 is uniquely induced in a cell density-dependent manner in keratinocyte cells and serves as an important regulator of keratinocyte cell proliferation and contact inhibition in vitro
We did not find the upregulated PDCD4 at high cell density in non-keratinocyte cell lines such as HEK293, HeLa and HepG2 (Figure 1E). These findings indicate that PDCD4 is induced at the transcriptional level in a cell density-dependent manner in keratinocytes, and this kind of regulation is a unique feature of epidermal keratinocytes
Summary
Programmed cell death 4 (PDCD4) is a tumor suppressor that has been implicated in the development of a broad spectrum of human tumors. PDCD4 was originally identified as a gene whose expression is induced in various types of apoptosis [1], and subsequently identified as a tumor suppressor in the JB6 mouse epidermal cell line model [2]. Many reports showed that decreased expression of PDCD4 is associated with many kinds of tumors, such as tumors of the lung, breast, colon and liver [5,6,7,8] These findings suggest that PDCD4 is a common tumor suppressor and plays an important role in carcinogenesis of a large spectrum of tumors. Apart from that, PDCD4 acts as a suppressor of translation by interacting with and inhibiting the eukaryotic translation initiation factor eIF4A [18,19] All these findings indicate that PDCD4 acquires the tumor suppressor properties by complicated regulation at multiple levels. Enhanced expression of PDCD4 are detected in both anagen hair follicle and transient hyperproliferative wound epidermis in vivo, which suggests the a steady-state regulating role of PDCD4 in epidermal homeostasis and wound healing
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