Abstract
Loss of epithelial differentiation and extracellular matrix (ECM) remodeling are known to facilitate cancer progression and are associated with poor prognosis in patients with lung cancer. We have identified Receptor-interacting serine/threonine protein kinase 4 (RIP4) as a regulator of tumor differentiation in lung adenocarcinoma (AC). Bioinformatics analyses of human lung AC samples showed that poorly differentiated tumors express low levels of RIP4, whereas high levels are associated with better overall survival. In vitro, lung tumor cells expressing reduced RIP4 levels showed enhanced activation of STAT3 signaling and had a greater ability to invade through collagen. In contrast, overexpression of RIP4 inhibited STAT3 activation, which abrogated interleukin-6-dependent induction of lysyl oxidase, a collagen cross-linking enzyme. In an autochthonous mouse model of lung AC initiated by Kras(G12D) expression with loss of p53, Rip4 knockdown tumors progressed to a poorly differentiated state marked by an increase in Hmga2, reduced Ttf1, and enrichment of genes regulating extracellular remodeling and Jak-Stat signaling. Tail vein injections of cells overexpressing Rip4 showed a reduced potential to invade and form tumors, which was restored by co-expression of Stat3. Altogether, our work has identified that loss of RIP4 enhances STAT3 signaling in lung cancer cells, promoting the expression of ECM remodeling genes and cancer dedifferentiation.
Highlights
Dedifferentiation of adenocarcinoma (AC) has been linked to various features of cancer development such as invasion, metastasis and stemness of cancer cells.[1,2] Mechanisms involved in dedifferentiation of lung tumors, the leading cause of cancer-related death,[3] are poorly understood
Treatment of lung cancer cells with Tumor necrosis factor (TNF)-related apoptosisinducing ligand led to RIP1-mediated Signal transducer and activator of transcription 3 (STAT3) activation resulting in increased cell invasion;[24] RIP2-mediated activation of NF-κB was crucial for triple-negative breast cancer cell motility and invasion.[25]
We investigated the expression of RIP4 in a compiled publicly available data set of human lung AC samples
Summary
Dedifferentiation of adenocarcinoma (AC) has been linked to various features of cancer development such as invasion, metastasis and stemness of cancer cells.[1,2] Mechanisms involved in dedifferentiation of lung tumors, the leading cause of cancer-related death,[3] are poorly understood. RIP3 mediated phosphorylation of RIP1 was shown to activate a pronecrotic complex downstream of TNF stimulation.[22]. RIP2 was shown to activate NF-κB in a Nucleotide-binding oligomerization domain-dependent manner.[23] Recent in vitro studies have hinted towards a role for RIP members in cancer invasion and metastasis. Mutations in RIP4 have been linked to an autosomal-recessive disorder called Bartsocas-Papas syndrome, which is characterized by loss of epidermal differentiation.[28,29] In cancer, RIP4 has been found to have conflicting roles: in diffuse large
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