Cells undergo anchorage-independent cell death or an anoikis, as they separate and move towards the epithelial surface [
1,
2]. Anoikis has a specific kind of physical characteristics similar to apoptosis, and it plays a crucial role in maintenance of normal tissue homeostasis and cell replacement [
2]. Anoikis occurs due to the inappropriate or faulty cellular interaction between Cell and ECM that might lead to the prevention of detached cells to the improper location. The current knowledge suggested that keratinocytes underwent anoikis when these normal cells failed to attach to ECM [
3]. Anoikis has a dominant involvement in the safeguard mechanisms of epithelial cells when they are in adherent culture, depending upon the interaction with ECM proteins. Due to anoikis resistance, some oral cavity cancer cell lines can grow in suspension due to the altered regulation of integrin and E-cadherin directed survival signaling [
4,
5].
Anchorage-independent cell growth is an important physiological process for cancer development. To assess the tumorigenicity, the unique property of tumor cells to grow in soft agar was considered as an in vitro test in immunosuppressed animals [
6]. During anoikis cells are detached from the ECM by mechanical forces or some other means to undergo apoptosis by extrinsic and intrinsic pathways. Failure to undergo anchorage-independent cell growth can be as an important hallmark of cancer owing to its property of invading through blood vessels and lymphatic stream. In order to support this fact, there are evidences that the passage of non-oncogenesis monkey kidney epithelial cells in suspension culture formed an anoikis-resistant line which leads to the generation of hypodermic tumors in nude mice [
7]. Moreover, melanoma cell suspension culture exhibited anoikis resistance and metastasis, when administered through tail veins of mice [
8]. While these earlier findings are supportive of our hypothesis, the correlation of in vitro anoikis resistance and metastasis potential has not been yet confirmed in an orthotropic in vivo tumor model. Literature suggested the involvement of TrkB protein in regulation of metastasis by screening of anoikis. In this current study, suitable experimental design and tumor model were developed to prove our hypothesis.
Psoriasin (S100A7), which belongs to S100 gene family [
9], was first isolated from psoriasis affected skin [
10]. It is an 11.4 kDa secretary protein, often responsible for inflammatory responses in the skin [
11,
12]. Furthermore, altered keratinocyte differentiation in skin was observed [
13,
14], and the differential expression of psoriasin was noted in squamous cell cancer (SCC) of bladder [
15] and in breast carcinoma [
16,
17]. Intensive studies revealed that increasing expression of psoriasin was well associated with early development of oncogenesis. Psoriasin was found to be up regulated in ductal carcinoma, but the expression of this protein was relatively low in adjacent invasive carcinoma [
17]. The altered expression of psoriasin was associated with epithelial cell differentiation. S100A2 and S100A4, member of S100 gene family were found to be deregulated in breast cancer [
18,
19]. Distinct changes in the expression profile of psoriasin were also noticed in benign tumors and high-grade DCIS [
17,
20]. Altered expression of psoriasin also appeared to be associated with poor prognosis in several invasive tumor predominantly in ERα-ve and ERß-ve tumors [
21]. Previous studies suggested that unlike the other category of S100 proteins counterpart, here psoriasin expression is generally controlled to the epithelial part of skin, breast, and bladder [
11,
15,
21‐
23]. In hyperplasia and dysplasia mediated pathological conditions, the expression of psoriasin was relatively low in normal epithelial cells whereas it was mostly up-regulated in keratinocytes in the epidermis. Earlier report revealed that functional activity of psoriasin is regulated by a small cluster of gene. Serial analysis of gene expression (SAGE) profiling demonstrated that above gene population is significantly up-regulated in actinic keratosis compared to normal skin [
13]. Only some of the genes, like psoriasin, were being expressed in the ‘epithelial differentiation complex’ region on chromosome 1q21 [
24]. It was observed that the main cellular transformation behind invasive phenomena is dedifferentiation that is involved as an integral part of this process [
25]. Several important factors were found to participate in controlling the regulation of psoriasin. Vitamin A derived metabolite retinoic acid included among these factors, which was found to be closely associated with the control of squamous cell differentiation [
26]. Psoriasin regulating factors include irradiation by UV, calcium and altered cell attachment to the skin [
26‐
30] and various physiological factors such as confluency, growth factor deprivation and loss of cellular attachment in breast epithelial cells [
16,
20]. Further evidences confirmed that cell stress due to UV radiation promotes activation of AP-1 transcription factor complex mediated by c-Jun/JNK pathway [
31]. It was noticed that skin tumorigenesis, progression, and invasion are caused due to the stimulation of the AP-1 pathway [
32]. Our study is trying to establish the importance of psoriasin in anoikis resistance and head and neck cancer tumor progression.