The relevance of lysophosphatidylcholine acyltransferase1 (LPCAT1), a cytosolic enzyme in the remodeling pathway of phosphatidylcholine metabolism, in oral squamous cell carcinoma (OSCC) is unknown. We investigated LPCAT1 expression and its functional mechanism in OSCCs. We analyzed LPCAT1 mRNA and protein expression levels in OSCC-derived cell lines. Immunohistochemistry was performed to identify correlations between LPCAT1 expression levels and primary OSCCs clinicopathological status. We established LPCAT1 knockdown models of the OSCC-derived cell lines (SAS, Ca9-22) for functional analysis and examined the association between LPCAT1 expression and the platelet-activating factor (PAF) concentration and PAF-receptor (PAFR) expression. LPCAT1 mRNA and protein were up-regulated significantly (p<0.05) in OSCC-derived cell lines compared with human normal oral keratinocytes. Immunohistochemistry showed significantly (p<0.05) elevated LPCAT1 expression in primary OSCCs compared with normal counterparts and a strong correlation between LPCAT1-positive OSCCs and tumoral size and regional lymph node metastasis. In LPCAT1 knockdown cells, cellular proliferation and invasiveness decreased significantly (p<0.05); cellular migration was inhibited compared with control cells. Down-regulation of LPCAT1 resulted in a decreased intercellular PAF concentration and PAFR expression. LPCAT1 was overexpressed in OSCCs and correlated with cellular invasiveness and migration. LPCAT1 may contribute to tumoral growth and metastasis in oral cancer.

Background: Glutamate decarboxylase 1 (GAD1), a rate-limiting enzyme in the production of γ-aminobutyric acid (GABA), is found in the GABAergic neurons of the central nervous system. Little is known about the relevance of GAD1 to oral squamous cell carcinoma (OSCC). We investigated the expression status of GAD1 and its functional mechanisms in OSCCs. Methods: We evaluated GAD1 mRNA and protein expressions in OSCC-derived cells using real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and immunoblotting analyses. To assess the critical functions of GAD1, i.e., cellular proliferation, invasiveness, and migration, OSCC-derived cells were treated with the shRNA and specific GAD1 inhibitor, 3-mercaptopropionic acid (3-MPA). GAD1 expression in 80 patients with primary OSCCs was analyzed and compared to the clinicopathological behaviors of OSCC. Results: qRT-PCR and immunoblotting analyses detected frequent up-regulation of GAD1 in OSCC-derived cells compared to human normal oral keratinocytes. Suppression of nuclear localization of β-catenin and MMP7 secretion was observed in GAD1 knockdown and 3-MPA-treated cells. We also found low cellular invasiveness and migratory abilities in GAD1 knockdown and 3-MPA-treated cells. In the clinical samples, GAD1 expression in the primary OSCCs was significantly (P < 0.05) higher than in normal counterparts and was correlated significantly (P < 0.05) with regional lymph node metastasis. Conclusions: Our data showed that up-regulation of GAD1 was a characteristic event in OSCCs and that GAD1 was correlated with cellular invasiveness and migration by regulating β-catenin translocation and MMP7 activation. GAD1 might play an important role in controlling tumoral invasiveness and metastasis in oral cancer.

The WW domain containing E3 ubiquitin protein ligase 2 (WWP2) encodes a member of the Nedd4 family of E3 ligases, which catalyzes the final step of the ubiquitination cascade. WWP2 is involved in tumoral growth with degradation of the tumor suppressor phosphatase and tensin homologue deleted on chromosome TEN (PTEN). However, little is known about the mechanisms and roles of WWP2 in human malignancies including oral squamous cell carcinomas (OSCCs). We found frequent WWP2 overexpression in all OSCC-derived cell lines examined that was associated with cellular growth by accelerating the cell cycle in the G1 phase via degradation of PTEN and activation of the PI3K/AKT signaling pathway. Our in vivo data of WWP2 silencing showed dramatic inhibition of tumoral growth with increased expression of PTEN. Our 104 primary OSCCs had significantly higher expression of WWP2 than their normal counterparts. Moreover, among the clinical variables analyzed, enhanced WWP2 expression was correlated with primary tumoral size and poor prognosis. These data suggested that WWP2 overexpression contributes to neoplastic promotion via the PTEN/PI3K/AKT pathway in OSCCs. WWP2 is likely to be a biomarker of tumoral progression and prognosis and a potential therapeutic target for development of anticancer drugs in OSCCs.

Background: The surveillance methods oral squamous cell carcinoma (OSCC) patients may be chosen by considering the risk for recurrence, and it is important to establish appropriate methods during the period in which latent/dormant cancer cells become more apparent. To investigate the appropriate surveillance of patients with OSCC based on the individual risk for recurrence and/or metastasis, we performed a retrospective cohort study after the complete surgical resection of OSCC as the primary treatment. Methods: The study was performed in 324 patients with OSCC who had been primarily treated with surgery from 2007 to 2020 at our hospital. We investigated the period, timing, and methods (visual examination, palpation and imaging using FDG-PET/CT or CECT) for surveillance in each case that comprised postsurgical treatment. Results: Regarding the time to occurrence of postsurgical events, we found that half of cases of local recurrence, cervical lymph node metastasis, and distant metastasis occurred within 200 days, and 75% of all of these events occurred within 400 days. However, the mean time for second primary cancer was 1589 days. The postsurgical events were detected earlier by imaging examinations than they were by visual examination and palpation. Conclusions: For the surveillance of patients with OSCC after primary surgery, it is desirable to perform FDG-PET/CT within 3–6 months and at 1 year after surgery and to consider CECT as an option in between FDG-PET/CT, while continuing history and physical examinations for about 5 years based on individual risk assessment.

Oral squamous cell carcinoma (OSCC) histopathologically accounts for ≥90% of oral cancer. Many clinicopathological risk factors for OSCC have also been proposed, and postoperative therapy is recommended in guidelines based on cancer stage and other risk factors. However, even if the standard treatment is provided according to the guidelines, a few cases rapidly recur or show cervical and distant metastasis. In this review article, we focus on the diversity of the origin of OSCC. We also discuss cancer stem cells (CSCs) as a key player to explain the malignancy of OSCC. CSCs are a subset of cancer cells that occupy a very small portion of the cancer mass and have characteristics of stem cells. When gene abnormalities accumulate in somatic stem cells, those cells transform into CSCs. CSCs as the origin of cancer then autonomously grow and develop into cancer. The histopathological phenotype of cancer cells is determined by the original characteristics of the somatic stem cells and/or surrounding environment. OSCC may be divided into the following three categories with different malignancy based on the origin of CSCs: cancer from oral epithelial stem cell-derived CSCs, cancer from stem cells in salivary gland-derived CSCs, and cancer from bone marrow-derived stem cell-derived CSCs.