ROCK2/rasHa co-operation induces malignant conversion via p53 loss, elevated NF-κB and tenascin C-associated rigidity, but p21 inhibits ROCK2/NF-κB-mediated progression

Abstract

ROCK2/rasHa cooperation induce malignant conversion via p53 loss, elevated NF-κβ and tenascin C-associated rigidity but p21 inhibits ROCK2/NF-κβ-mediated progression. Oncogene, 36, pp. 2529Oncogene, 36, pp. -2542Oncogene, 36, pp. . (doi:10.1038Oncogene, 36, pp. /onc.2016 This is the author's final accepted version.There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.http://eprints.gla.ac.uk/129163/ Malignancy depended on ROCK er /p-Mypt1 expression, as cessation of 4HT-treatment induced disorganised tissue architecture and p21-associated differentiation in wdSCCs; yet tenascin C retention in connective tissue ECM suggests the rigidity laid down for conversion persists. Novel papilloma outgrowths appeared expressing intense, basal-layer p21 which confined endogenous ROCK2/p-Mypt1/NF-κβ to supra-basal layers, and was paralleled by restored basal-layer p53. In later SCCs, 4HT-cessation became irrelevant as endogenous ROCK2 expression increased, driving progression via p21 loss, elevated NF-κβ expression and tenascin C-associated rigidity; with p-Mypt1 inactivation/actinomyosin-mediated contractility to facilitate invasion. However, p21-associated inhibition of early-stage malignant progression and the intense expression in papilloma outgrowths, identifies a novel, significant antagonism between p21 and ras Ha /ROCK2/NF-κβ signalling in skin 3 carcinogenesis. Collectively these data show that ROCK2 activation induces malignancy in ras Ha -initiated/promoted papillomas in the context of p53 loss and novel NF-κβ expression; whilst increased tissue rigidity and cell motility/contractility help mediate tumour progression.4

Disease-specific alteration of karyopherin-α subtype establishes feed-forward oncogenic signaling in head and neck squamous cell carcinoma

“…8). An involvement of NF-κB in SCC initiation and progression in vivo was previously demonstrated [37,38]. Since KPNA4 functions as a transporter for these two oncoproteins, how these TFs coordinate in the evolution of SCC should be examined in future studies.…”

RAS induced senescence of skin keratinocytes is mediated through Rho‐associated protein kinase (ROCK)

“…Targeting ROCK2 and oncogenic RAS to mouse epidermis enhanced malignant conversion associated with loss of p21. 51 Similarly, while epidermal deletion of RhoA increased skin tumor incidence, it encouraged tumor invasion through a compensatory increase in cutaneous RhoB. 52 These data suggested that Rho/ROCK signaling can have differential effects on benign and malignant tumor development.…”

Roles of Rho‑associated kinase in lung cancer (Review)

“…ROCK activation is positively associated with tumor growth (13,(41)(42)(43), and a growing number of studies continue to lend credence to the importance of the ROCK signaling pathway in lung cancer development. ROCK is one of the Rho pathway genes that is significantly upregulated in a number of KRAS mutant NSCLC cell lines (44,45), several NSCLC animal models (15,46), and tumor tissues derived from patients with NSCLC (37,47).…”

“…ROCK plays an essential role in carcinogenesis, particularly in promoting cancer cell motility that causes metastasis. ROCK is an effector of the small GTPase Rho and has been studied in various malignancies, such as breast (12), skin (13), liver (14) and lung cancer (15). Studies on lung cancer usually use NSCLC cell lines or tissue biopsies from patients with NSCLC to assess changes in the proliferation, migration, and growth of cancer following the inhibition of knockdown of ROCK (16)(17)(18)(19)(20)(21).…”