Abstract
Emerging evidence suggests that the cancer stem cells (CSCs) are key culprits of cancer metastasis and drug resistance. Understanding mechanisms regulating the critical oncogenic pathways and CSCs function could reveal new diagnostic and therapeutic strategies. We now report that miR-22, a miRNA critical for hair follicle stem/progenitor cell differentiation, promotes tumor initiation, progression, and metastasis by maintaining Wnt/β-catenin signaling and CSCs function. Mechanistically, we find that miR-22 facilitates β-catenin stabilization through directly repressing citrullinase PAD2. Moreover, miR-22 also relieves DKK1-mediated repression of Wnt/β-catenin signaling by targeting a FosB-DKK1 transcriptional axis. miR-22 knockout mice showed attenuated Wnt/β-catenin activity and Lgr5+ CSCs penetrance, resulting in reduced occurrence, progression, and metastasis of chemically induced cutaneous squamous cell carcinoma (cSCC). Clinically, miR-22 is abundantly expressed in human cSCC. Its expression is even further elevated in the CSCs proportion, which negatively correlates with PAD2 and FosB expression. Inhibition of miR-22 markedly suppressed cSCC progression and increased chemotherapy sensitivity in vitro and in xenograft mice. Together, our results revealed a novel miR-22-WNT-CSCs regulatory mechanism in cSCC and highlight the important clinical application prospects of miR-22, a common target molecule for Wnt/β-catenin signaling and CSCs, for patient stratification and therapeutic intervention.
Highlights
Due to its higher risk of recurrence and metastasis characteristics, cutaneous squamous cell carcinoma is responsible for the majority of non-melanoma skin cancers (NMSC) related deaths even it only accounts for 20% of the cases [1, 2]
RESULTS miR-22 is upregulated in cutaneous squamous cell carcinoma (cSCC) and correlated with cSCC progression and poor prognosis Stem cells from hair follicle and epidermis could both contribute to cSCC development, we wonder whether miR-22, a critical regulator of hair follicle stem cells (HFSCs) differentiation, could be involved in cSCC occurrence
We analyzed available head and neck squamous cell carcinoma (HNSCC) samples in the The Cancer Genome Atlas (TCGA) database and revealed that miR-22 was highly expressed in HNSCC compared to normal adjacent tissues, and miR-22high tumors were associated with worse clinical outcomes than miR22low tumors, with regard to 5-year overall survival (Fig. 1F and Supplementary Fig. 1c, d)
Summary
Due to its higher risk of recurrence and metastasis characteristics, cutaneous squamous cell carcinoma (cSCC) is responsible for the majority of non-melanoma skin cancers (NMSC) related deaths even it only accounts for 20% of the cases [1, 2]. Accumulating evidence suggests that metastasis and resistance to chemotherapy of cSCC are mainly attributed to the role of constitutive activated oncogenic pathways and CSCs [3,4,5,6]. Latil et al found that Lgr5-positive hair follicle stem cells (HFSCs) prefer to initiate cSCC with high metastatic potential when KRasG12D expression and p53 deletion were incorporated in a cell-typespecific manner [7]. In this context, the over-activated RAS signaling is the key premise of tumor formation and metastasis. The miRNA expression profiles during cSCC development and their potential therapeutic significance remains to be explored
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