Shyh-Kuan Tai

Regulation of Excision Repair Cross-Complementation Group 1 by Snail Contributes to Cisplatin Resistance in Head and Neck Cancer

Purpose: We investigated the mechanism and clinical significance of the epithelial-mesenchymal transition (EMT)-induced chemoresistance in head and neck squamous cell carcinoma (HNSCC). Experimental Design: The correlation between the expression of different EMT regulators and chemoresistance genes, such as excision repair cross complementation group 1 (ERCC1), was evaluated in cancer cell lines from the NCI-60 database and four human HNSCC cell lines. Ectopic expression of Snail or short-interference RNA-mediated repression of Snail or ERCC1 was done in HNSCC cell lines. Cell viability was examined for cells after cisplatin treatment. A luciferase reporter assay and chromatin immunoprecipitation were used to identify the transcriptional regulation of ERCC1 by Snail. Immunohistochemical analysis of Snail, Twist1, ERCC1, hypoxia inducible factor-1 α (HIF-1α), and NBS1 were done in samples from 72 HNSCC patients receiving cisplatin-based chemotherapy. Results: The correlation between the expression of Snail and ERCC1 was confirmed in different cell lines, including HNSCC cells. In HNSCC cell lines, overexpression of Snail in the low endogenous Snail/ERCC1 cell lines FaDu or CAL-27 increased ERCC1 expression, and hypoxia or overexpression of NBS1 also upregulated ERCC1. Knockdown of Snail in the high endogenous Snail/ERCC1 cell line OECM-1 downregulated ERCC1 expression and attenuated cisplatin resistance. Furthermore, suppression of ERCC1 in Snail- or NBS1-overexpressing HNSCC cells enhanced sensitivity to cisplatin. Snail directly regulated ERCC1 transcription. In patients with HNSCC, coexpression of Snail and ERCC1 correlated with cisplatin resistance and a poor prognosis. Conclusions: Activation of ERCC1 by Snail is critical in the generation of cisplatin resistance of HNSCC cells. Clin Cancer Res; 16(18); 4561–71. ©2010 AACR.

Risks and clinical implications of perineural invasion in T1‐2 oral tongue squamous cell carcinoma

Risks of perineural invasion (PNI) in T1‐2 oral tongue squamous cell carcinoma (SCC) have not been specifically elucidated.

Chromosome Instability Modulated by BMI1–AURKA Signaling Drives Progression in Head and Neck Cancer

Chromosomal instability (CIN) is widely considered a hallmark of cancer, but its precise roles in cancer stem cells (CSC) and malignant progression remain uncertain. BMI1 is a member of the Polycomb group of chromatin-modifier proteins that is essential for stem cell self-renewal. In human cancers, BMI1 overexpression drives stem-like properties associated with induction of epithelial-mesenchymal transition (EMT) that promotes invasion, metastasis, and poor prognosis. Here, we report that BMI1 mediates its diverse effects through upregulation of the mitotic kinase Aurora A, which is encoded by the AURKA gene. Two mechanisms were found to be responsible for BMI1-induced AURKA expression. First, BMI1 activated the Akt pathway, thereby upregulating AURKA expression through activation of the β-catenin/TCF4 transcription factor complex. Second, BMI1 repressed miRNA let-7i through a Polycomb complex-dependent mechanism, thereby relieving AURKA expression from let-7i suppression. AURKA upregulation by BMI1 exerts several effects, including centrosomal amplification and aneuploidy, antiapoptosis, and cell-cycle progression through p53 degradation and EMT through stabilization of Snail. Inhibiting Aurora A kinase activity attenuated BMI1-induced tumor growth in vivo. In clinical specimens of head and neck cancer, we found that coamplification of BMI1 and AURKA correlated with poorer prognosis. Together, our results link CSCs, EMT, and CIN through the BMI1-AURKA axis and suggest therapeutic use from inhibiting Aurora A in head and neck cancers, which overexpress BMI1.

Effectiveness of narrow band imaging in patients with oral squamous cell carcinoma after treatment

We evaluated the effectiveness of narrow band imaging (NBI) in patients with oral squamous cell carcinoma (OSCC) after treatment.

Positron emission tomography in surveillance of head and neck squamous cell carcinoma after definitive chemoradiotherapy.

We assessed the role of 18F‐fluoro‐deoxy‐glucose positron emission tomography (PET) in detecting head and neck squamous cell carcinoma (HNSCC) after definitive chemoradiotherapy (CRT).

Persistent Krüppel-like factor 4 expression predicts progression and poor prognosis of head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is one prevalent human cancer worldwide. No molecular markers are presently used for predicting prognosis in HNSCC. Krüppel‐like factor 4 (KLF4) is a transcription factor with diverse physiological functions, and possesses opposing roles in different human cancers. The expression and roles of KLF4 in HNSCC remain to be elucidated. In this study, immunohistochemical (IHC) analysis of KLF4 in 62 HNSCC was firstly performed. IHC results demonstrated that 42 (67.7%) had decreased KLF4 expression compared with surrounding normal epithelium, while persistent KLF4 expression was demonstrated in 20 (32.3%). The IHC results were further verified by Western blot and real‐time PCR analyses to confirm the robustness of staining and interpretation. Interestingly, persistent KLF4 expression independently correlated with a worse disease‐specific survival (P = 0.005), especially in patients with advanced disease. In consistent with clinical observation, all five HNSCC cell lines tested revealed a low level of baseline KLF4 expression. Moreover, enforced KLF4 expression in cell line SAS significantly increased in vitro migration/invasion abilities, multi‐drug resistance, and in vivo tumorigenicity. These results clearly illustrate that persistent KLF4 expression predicts poor prognosis and confers aggressiveness in HNSCC. Our data therefore provides valuable information that HNSCC with persistent KLF4 expression might require intensified combination treatment in future practice. (Cancer Sci 2011; 102: 895–902)

Second Primary Malignancies in Squamous Cell Carcinomas of the Tongue and Larynx: An Analysis of Incidence, Pattern, and Outcome

Background: Head and neck cancer patients have a higher risk of developing a second primary malignancy (SPM) than the general population. This study was conducted to identify the characteristics of SPM and its impact on survival in patients with squamous cell carcinoma of the tongue (TSCC) and larynx (LSCC). Methods: A retrospective study was conducted of 538 patients who were treated by surgery primarily for TSCC (n = 146) and LSCC (n = 392) from 1990 to 2000. The incidence, site, and overall survival of SPMs were evaluated. Results: Seventy‐seven patients developed SPM during the follow‐up period (median, 73 months), including 18 (12%) with TSCC and 59 (15%) with LSCC. Fifty‐six percent of SPMs of the TSCC group appeared in the oral cavity. Among the SPMs of LSCC patients, 54% developed in the lung (31%) and larynx (24%). The 5‐year overall survival after the diagnosis of SPM in the head and neck was 39%, compared to 29% for SPM in other areas (p = 0.010). Conclusion: SPMs after treatment of TSCC and LSCC are similar in incidence but distinct in pattern. SPMs within the head and neck are associated with a better prognosis than those outside this area.

Perineural invasion in T1 oral squamous cell carcinoma indicates the need for aggressive elective neck dissection.

Observation or elective neck dissection (END) for cN0 neck remains controversial for the treatment of T1-2 oral squamous cell carcinoma (OSCC). Perineural invasion (PNI) has been recognized as a poor prognostic factor for OSCC. However, its significance in T1 OSCC remains unclear. A detailed histologic reevaluation of PNI was carried out in 307 patients with T1-2 OSCC who received surgical treatment between June 2001 and January 2009. We found that the presence of PNI correlated with cervical lymph node metastasis in both T1 and T2 OSCC, with a lower PNI-positive rate in T1 (17.1% vs. 36.6%; P<0.001). Importantly, observation for cN0 neck was used twice as often in T1 than in T2 patients (47.4% vs. 22.8%; P<0.001). Although patients with T1 OSCC achieved significantly better outcomes, PNI correlated with neck recurrence and poor disease-specific survival (DSS) only in T1 (P<0.001 and P<0.0001) but not in T2 patients (P=0.399 and 0.1478). Of the 146 patients with T1 OSCC, PNI independently predicted cervical lymph node metastasis, neck recurrence, and poor DSS. END significantly reduced neck recurrence of T1 OSCC in PNI-positive (P=0.001) but not in PNI-negative (P=0.114) patients. In addition, END improved the 5-year DSS of T1 OSCC more in PNI-positive than in PNI-negative patients (16.2% vs. 5.4%). Our results indicate that PNI independently predicts a poor prognosis in T1 OSCC patients who are potentially curable but tend to be treated conservatively. For its efficacy in improving treatment outcomes, aggressive END is indicated for T1 OSCC patients at the presence of PNI.

Cisplatin-based chemotherapy versus cetuximab in concurrent chemoradiotherapy for locally advanced head and neck cancer treatment.

Background and Purpose. This study aimed to analyze survival, clinical responses, compliance, and adverse effects in locally advanced head and neck cancer (LAHNC) patients treated with split-dose cisplatin-based concurrent chemoradiation therapy (SD-CCRT) or cetuximab with concurrent radiation therapy (BioRT). Materials and Methods. We retrospectively evaluated 170 LAHNC patients diagnosed between January 1, 2009, and July 31, 2012: 116 received CCRT and 54 received BioRT. Results. Complete response rates were similar in the SD-CCRT and BioRT groups (63.8% versus 59.3%; P = 0.807), and locoregional relapse rates were 18.1% and 13.0%, respectively (P = 0.400). The 3-year relapse-free survival rate was 65.8% in the SD-CCRT group and 65.5% in the BioRT group, respectively (P = 0.647). The 3-year overall survival rate was 78.5% in the SD-CCRT group and 70.9% in the BioRT group, respectively (P = 0.879). Hematologic side effects were significantly more frequent in the SD-CCRT than in the BioRT group. Mucositis frequency was similar. Conclusions. Primary SD-CCRT and BioRT both showed good clinical response and survival. Hematologic toxicities were more frequent, but tolerable, in the SD-CCRT group. Both groups showed good compliance.

Different patterns of second primary malignancy in patients with squamous cell carcinoma of larynx and hypopharynx.

PURPOSE The aim of the present study was to compare the incidence, patterns, and survival of second primary malignancy (SPM) in patients with squamous cell carcinoma of the larynx (LSCC) and hypopharynx (HPSCC). METHODS We retrospectively review the medical record of 581 previously untreated patients with LSCC (392 cases) and HPSCC (189 cases) who received primary surgery with or without postoperative radiotherapy from 1990 to 2000. Data including age, sex, risk factors, subsites and TNM stage of primary tumor, treatment, site and incidence of SPM, and prognosis were collected from medical charts. RESULTS Groups with HPSCC had a higher incidence (4.2% vs 2.9% annual rate) and shorter median time (30 vs 59 months) developing SPM rather than LSCC. Fifty-five percent of the SPM occurred in the respiratory axis in LSCC, and 66% developed in the digestive axis in HPSCC. The factors influencing the appearance of SPM included early T stage, tobacco use, and less tumor recurrence. Long-term survival was poorer in those with than without SPM (38% vs 49% at 10 years). CONCLUSIONS There is a tendency for SPM to occur in the respiratory axis (lung and larynx) in LSCC and in the digestive axis (oral cavity, pharynx, and esophagus) in HPSCC. This information is important for posttreatment follow-up.