RhoC: a fascinating journey from a cytoskeletal organizer to a Cancer stem cell therapeutic target

Abstract

Tumor heterogeneity results in differential response to therapy due to the existence of plastic tumor cells, called cancer stem cells (CSCs), which exhibit the property of resistance to therapy, invasion and metastasis. These cells have a distinct, signaling network active at every stage of progression. It is difficult to envisage that the CSCs will have a unique set of signaling pathways regulating every stage of disease progression. Rather, it would be easier to believe that a single pivotal pathway having significant contribution at every stage, which can further turn on a battery of signaling mechanisms specific to that stage, would be instrumental in regulating the signaling network, enabling easy transition from one state to another. In this context, we discuss the role of RhoC which has contributed to several phenotypes during tumor progression. RhoC (Ras homolog gene family member C) has been widely reported to regulate actin organization. It has been shown to impact the motility of cancer cells, resultantly affecting invasion and metastasis, and has contributed to carcinoma progression of the breast, pancreas, lung, ovaries and cervix, among several others. The most interesting finding has been its indispensable role in metastasis. Also, it has the ability to modulate various other phenotypes like angiogenesis, motility, invasion, metastasis, and anoikis resistance. These observations suggest that RhoC imparts the plasticity required by tumor cells to exhibit such diverse functions based on microenvironmental cues. This was further confirmed by recent reports which show that it regulates cancer stem cells in breast, ovary and head and neck cancers. Studies also suggest that the inhibition of RhoC results in abolition of advanced tumor phenotypes. Our review throws light on how RhoC, which is capable of modulating various phenotypes may be the apt core signaling candidate regulating disease progression. Additionally, mice studies show that RhoC is not essential for embryogenesis, giving scope for its development as a possible therapeutic target. This review thus stresses on the need to understand the protein and its functioning in greater detail to enable its development as a stem cell marker and a possible therapeutic target .

RNF180 mediates STAT3 activity by regulating the expression of RhoC via the proteasomal pathway in gastric cancer cells

“…RhoC is a guanosine triphosphatase that can modulate the proliferation, differentiation, and apoptosis of normal cells [21][22][23] . Previous studies have shown that the Rhofamily of small GTPases has an essential role in transmitting the VEGF signals downstream to angiogenesis 24 .…”

Regulation Networks Driving Vasculogenic Mimicry in Solid Tumors

“…RhoC (Ras homolog gene family member C) regulates cytoskeletal organization and affects the motility of cancer cells favoring invasion and metastasis as well as progression and VM formation (74). In hepatocellular carcinoma (HCC), vascular channels were formed, and these vessels were associated with RhoC FAK/Paxillin signaling regulation as well as with high expression of RhoC/ROCK2, VE-cadherin, and MMP2 mediated by ERK/MMPs signaling (75).…”

RhoC modulates metabolic networks in cervical cancer by transcriptionally regulating the expression of genes involved in metabolism

“…Our work on the role of RhoC in tumor progression along with other abundant literature, support the contribution of RhoC in determining the sequence of events during tumor progression. Beginning from tumor formation till metastasis, RhoC is required for all the intervening steps, which include invasion, anoikis resistance, intravasation, extravasation and homing (Reymond et al, 2015; Srivastava et al, 2010; Thomas, Pranatharthi, Ross, & Srivastava, 2019). We have recently observed that RhoC provides radioprotection to tumor cells, a hallmark of cancer stem cells (Pranatharthi et al, 2019).…”

“…Similarly the regulation of metastasis by RhoC has been well elaborated in several tumors (Clark, Golub, Lander, & Hynes, 2000; Hakem et al, 2005; Hoshino, Koshikawa, & Seiki, 2010; Iiizumi et al, 2008; Islam, Sharma, Kumar, & Teknos, 2013; Kleer et al, 2006; Kleer et al, 2002; Rosenthal et al, ; Wu, Wu, Kumar-Sinha, Chinnaiyan, & Merajver, 2004; Xing et al, ; Yao, Dashner, van Golen, & van Golen, 2006), where they show that alteration in the expression of RhoC results in changes in metastasis. Similarly, its role in regulating angiogenesis, anoikis resistance and cancer stem cell maintenance is undisputable (Thomas et al, 2019). The role of Notch1 in regulating RhoC in cervical cancer illustrates its upstream regulatory mechanism (Srivastava et al, 2010) as there is no driver mutation observed in RhoC as per the TCGA data, 2019.…”